Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer
Stefan Eser, Nina Reiff, et al.
Read it. It tells you that not only the implications of a stimulation of one molecule change with the tissue because of tissue specific genetic silencing , but also changes can occur on different RAS family member (NRas or Hras) leading to different meaning in terms of consequence for the cell.
Another discrimination level is that many types of stimulation can induce the same pathway. C-JUN can be induced by radiation, chemical, hypoxia or infection. Any thing that is considered stressful, including lack of extracellular stimulation. This last point is very important in the Central nervous system where pre-synaptic stimulation is critical for post synaptic neurons. Lack of stimulation induces an inflammatory process in both the neuron and the glial cell. In the glial cell, the myelin sheath is scarily attacked or no longer formed.
The duplicity phenomena occurs particularly at the cellular membrane where many receptors would be stimulated by several stimulants and vice versa (many stimulants for same receptor). Only the cell and its tissue type know what to give out!
*New study concurs that mammogram should be done every 2 years and after 50 years of age. That only those women with dense breasts should start at 40 years of age and annually. The controversy dance is fueled once again and I don't blame anyone! We have seen cases of course which did not fit these prescription. Why change things that work.
Tuesday, March 19, 2013
Sunday, March 17, 2013
PANCREATIC CANCER GENE (CONTINUED)
1' KRT20: keratin related gene, most likely of an early expression in neoplastic transformation
more predictive and diagnostic than of less therapeutic potential.
2-TEM 7: The blood vessels of Tumors seems to have an exclusive marker called Tumor Endothelial Marker or TEM. Target therapy directed at this stuff may lead tumor to anoxic death by closing these vessels, at least that the wish of researchers, will follow their efforts!
Certainly this used as serologic marker or radiologically, can locate metastatic lesions.
3-MAP2K4" direct activator of the MAPK/c-JUNK through MAP8& 14. (Not the standard MAPK1)
but it also interact with an anchor called Filamin Though FLNC, filamin is actin binding protein, raising the issue of whether or not it is using this tract to quickly influence the Nucleus or whether it allows it to phosphorylate things right there! we know its expression is, like the MTOR stimulated path, preserving survival! Does this open the door to MTOR Inhibitor in Pancreatic cancer? Does expression of this pathway, an opportunity to introduce MTOR inhibitors?
4-BAT-26
please read this:
"BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines" by
9-ERBB2
10-GAS
11-TM4SF5
more predictive and diagnostic than of less therapeutic potential.
2-TEM 7: The blood vessels of Tumors seems to have an exclusive marker called Tumor Endothelial Marker or TEM. Target therapy directed at this stuff may lead tumor to anoxic death by closing these vessels, at least that the wish of researchers, will follow their efforts!
Certainly this used as serologic marker or radiologically, can locate metastatic lesions.
3-MAP2K4" direct activator of the MAPK/c-JUNK through MAP8& 14. (Not the standard MAPK1)
but it also interact with an anchor called Filamin Though FLNC, filamin is actin binding protein, raising the issue of whether or not it is using this tract to quickly influence the Nucleus or whether it allows it to phosphorylate things right there! we know its expression is, like the MTOR stimulated path, preserving survival! Does this open the door to MTOR Inhibitor in Pancreatic cancer? Does expression of this pathway, an opportunity to introduce MTOR inhibitors?
4-BAT-26
please read this:
"BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines" by
BAT 26 IS THEREFORE AN INDICATOR OF MICRO-SATELLITE INSTABILITY STATUS IN CANCER.
--------------------------------------------------------------------------------------------
5-ALOX12
6-TP53
7-BIRC5
8-NME19-ERBB2
10-GAS
11-TM4SF5
An interesting set of Circumstances
------------------------------------
We seem to live an interesting time, unusual things happening, the government is late doing stuff. Although it claims it is pro-business, licenses are delayed and the emphasis seems to crack down, and pay less. Shrinking everything seems to be the impetus!
The most interesting scenario is what is happening with the IRS. Because I need to meet some money demands, I filed my taxes early in February or as soon as I got my W-2 and related 1099. 4 weeks after I filed, I got a text on my phone that the IRS has rejected my filing. I thought it was a joke but sure enough I got confirmation through my e-mail and from the IRS office. We must live an interesting revolution! When the IRS is now evading tax-filing. It used to be that if you do something incorrect, the IRS corrects it. I had come to expect that and normally sent my best evaluation for their smart correction. NOW if they are rejecting Tax submission where the hell should I go? The interesting thing is, according to their not, a rejected Tax file is not a "Filing, and the can still charge me for late filing and evasion if not refiled". Can you possibly evade Taxes when you are repeatedly trying to file? The IRS is getting it both ways I believe. They refuse to do the work, and still threaten to punish me! What in the world is going on? If you figure it out, help me!
------------------------------------
We seem to live an interesting time, unusual things happening, the government is late doing stuff. Although it claims it is pro-business, licenses are delayed and the emphasis seems to crack down, and pay less. Shrinking everything seems to be the impetus!
The most interesting scenario is what is happening with the IRS. Because I need to meet some money demands, I filed my taxes early in February or as soon as I got my W-2 and related 1099. 4 weeks after I filed, I got a text on my phone that the IRS has rejected my filing. I thought it was a joke but sure enough I got confirmation through my e-mail and from the IRS office. We must live an interesting revolution! When the IRS is now evading tax-filing. It used to be that if you do something incorrect, the IRS corrects it. I had come to expect that and normally sent my best evaluation for their smart correction. NOW if they are rejecting Tax submission where the hell should I go? The interesting thing is, according to their not, a rejected Tax file is not a "Filing, and the can still charge me for late filing and evasion if not refiled". Can you possibly evade Taxes when you are repeatedly trying to file? The IRS is getting it both ways I believe. They refuse to do the work, and still threaten to punish me! What in the world is going on? If you figure it out, help me!
NOMENCLATURE OF GENE (III ), PANCREATIC CANCER!
BETA 4 INTEGRIN: a gene that does more than being an adhesion molecules
it is the road to a poorly described and not well recognized pathway
Not only it gives Hypertrophy but epidermolysis goes through this intergrin, it participates in the ERBB pathways. Mark my word these are critical pathways in pancreatic cancers.
MTIF GIVES YOU MOTIVES TO AFTER IT!
MAKING THE ERBIN A PLAUSIBLE TARGET.
MAKING ALSO A STRONGER CASE THAT MEMBRANE CYTOSKELETON SHOULD BE A GOOD TARGET BECAUSE OF THE WAY IT DRIVES ITS PATHWAY NOT THROUGH THE CYTOSOL( ALTHOUGH THERE IS A SECONDARY RAS/MAPK STIMULATION,) BUT THE PATHWAY HERE IS THROUGH THE RETICULUM ENDOTHELIUM DIRECTLY TO THE NUCLEUS! CONCEPTUALLY, AN ANTIBODY TO LAMININ ATTACHED TO A SUBUNIT OF A LIPOLYTIC COMPOUND SHOULD HAVE A THERAPEUTIC OR CHEMICAL EFFECT AT THIS LEVEL. AN INTERESTING APPROACH. CHANCES ARE IT MAY ALSO HAVE A STRONG IMPACT ON THE WNT-PATHWAY WHICH TRAVELS CLOSE BY AND IS IMPORTANT IN BREAST CANCER!
MTA-1: THIS IS A REAL OPPORTUNITY
Here the cell stopped fooling around trying to lie to you. Here the cell says to you this is one of my ways to metastasize. yes this is my gene to metastasize and I will work like any CBF like molecule by attaching to DNA and make me protein that will have me spread like wild fire! And by the way, I will use a growth hormone like Estrogen. No kidding around.
"MTA1 has been shown to interact with HDAC1,[4][5] Histone deacetylase 2,[4][6][5] MTA2,[4] Estrogen receptor alpha[7][5] and MNAT1.[8] MTA1 has also been shown to inhibit SMAD7 at the transcriptional level[9]"
IT DOES NEED TGF TO WORK, TGF IS FOR LOCAL GROWTH ANYWAY, THAT IS WHY IT BLOCKS THE SMAD.
SPINT2
Mutation at SPINT2 leads to significant Malignant Ascites and peritoneal invasion, SPINT 2 is a suppressor of this phenomena. On the Intestinal membrane deficiency of SPINT2 leads to sodium induced/containing diarrhea. This is also true in Ovarian cancer or peritoneal based tumors. Targeting this is better than trying Avastin, a blind approach when it comes to effusion management.
MMP11
A metalloproteinase, aimed at breaking down extracellular matrix and be on the move. Targeting MMP for cancer has proven futile. The cell is not stupid, it does not put out things that are going to hunt it! It builds first a strong inhibitor to metalloproteinases. In fact, the lack of inhibitors has been recognized as the main pathogenesis of TTP. With the ADAMs being the integrins involved! and next is that Inhibitor which is, of course, expressed in pancreatic cancer.
TIMP1
TIMP metallopeptidase inhibitor 1, also known as TIMP1, a tissue inhibitor of metalloproteinases, is a glycoprotein that is expressed from the several tissues of organisms.
This protein a member of the TIMP family. The glycoprotein is a natural inhibitor of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function.
==============
PRKCA see PRKCG
Here Phorbol esters, diacylglycerol, and calcium become important for the cell performance of various functions. Did I mention few targets, I truly believe I did!
CDH1 The Cadherin by excellence, not only important as adhesion molecule and role in metastasis. Its role is amplified by what else anchors here such as Vinculin, and others molecules such as Plakoglobins, amplifying the role. Remember even Cytochrome C is anchored at the mitochondrial membrane and its release leads to apoptosis!
The anchors are legitimate targets therefore, and brings to mind NACA1 in the anchoring to Histone deacetyl transferase (SEE OUR LEUKEMIA SECTION) CDH13 THAT'S ANOTHER BALL GAME ALL TOGETHER. THE CELL TWEACKS SOMETHING AND IT IS ANOTHER BALL GAME ALL TOGETHER!
==========================
it is the road to a poorly described and not well recognized pathway
The LysRS-Ap4A-MITF signaling pathway
The LysRS-Ap4A-MITF signaling pathway was first discovered in mast cells, in which , the MAPK pathway is activated upon allergen stimulation. Lysyl-tRNA synthetase (LysRS), which normally resides in the multisynthetase complex with other tRNA synthetases, is phosphorylated on Serine 207 in a MAPK-dependent manner.[30] This phosphorylation causes LysRS to change its conformation, detach from the complex and translocate into the nucleus, where it associates with the MITF-HINT1 inhibitory complex. The conformational change switches LysRS activity from aminoacylation of Lysine tRNA to diadenosine tetraphosphate (Ap4A) production. Ap4A binds to HINT1, which releases MITF from the inhibitory complex, allowing it to transcribe its target genes.[31] Activation of the LysRS-Ap4A-MITF signaling pathway by isoproterenol has been confirmed in cardiomyocytes, where MITF is a major regulator of cardiac growth and hypertrophy.[32][33](wikipedia)Not only it gives Hypertrophy but epidermolysis goes through this intergrin, it participates in the ERBB pathways. Mark my word these are critical pathways in pancreatic cancers.
MTIF GIVES YOU MOTIVES TO AFTER IT!
MAKING THE ERBIN A PLAUSIBLE TARGET.
MAKING ALSO A STRONGER CASE THAT MEMBRANE CYTOSKELETON SHOULD BE A GOOD TARGET BECAUSE OF THE WAY IT DRIVES ITS PATHWAY NOT THROUGH THE CYTOSOL( ALTHOUGH THERE IS A SECONDARY RAS/MAPK STIMULATION,) BUT THE PATHWAY HERE IS THROUGH THE RETICULUM ENDOTHELIUM DIRECTLY TO THE NUCLEUS! CONCEPTUALLY, AN ANTIBODY TO LAMININ ATTACHED TO A SUBUNIT OF A LIPOLYTIC COMPOUND SHOULD HAVE A THERAPEUTIC OR CHEMICAL EFFECT AT THIS LEVEL. AN INTERESTING APPROACH. CHANCES ARE IT MAY ALSO HAVE A STRONG IMPACT ON THE WNT-PATHWAY WHICH TRAVELS CLOSE BY AND IS IMPORTANT IN BREAST CANCER!
MTA-1: THIS IS A REAL OPPORTUNITY
Here the cell stopped fooling around trying to lie to you. Here the cell says to you this is one of my ways to metastasize. yes this is my gene to metastasize and I will work like any CBF like molecule by attaching to DNA and make me protein that will have me spread like wild fire! And by the way, I will use a growth hormone like Estrogen. No kidding around.
"MTA1 has been shown to interact with HDAC1,[4][5] Histone deacetylase 2,[4][6][5] MTA2,[4] Estrogen receptor alpha[7][5] and MNAT1.[8] MTA1 has also been shown to inhibit SMAD7 at the transcriptional level[9]"
IT DOES NEED TGF TO WORK, TGF IS FOR LOCAL GROWTH ANYWAY, THAT IS WHY IT BLOCKS THE SMAD.
SPINT2
Mutation at SPINT2 leads to significant Malignant Ascites and peritoneal invasion, SPINT 2 is a suppressor of this phenomena. On the Intestinal membrane deficiency of SPINT2 leads to sodium induced/containing diarrhea. This is also true in Ovarian cancer or peritoneal based tumors. Targeting this is better than trying Avastin, a blind approach when it comes to effusion management.
MMP11
A metalloproteinase, aimed at breaking down extracellular matrix and be on the move. Targeting MMP for cancer has proven futile. The cell is not stupid, it does not put out things that are going to hunt it! It builds first a strong inhibitor to metalloproteinases. In fact, the lack of inhibitors has been recognized as the main pathogenesis of TTP. With the ADAMs being the integrins involved! and next is that Inhibitor which is, of course, expressed in pancreatic cancer.
TIMP1
TIMP1
From Wikipedia, the free encyclopedia
| TIMP metallopeptidase inhibitor 1 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
 PDB rendering based on 1d2b. |
|||||||||||
|
|||||||||||
| Identifiers | |||||||||||
| Symbols | TIMP1; CLGI; EPA; EPO; HCI; TIMP | ||||||||||
| External IDs | OMIM: 305370 MGI: 98752 HomoloGene: 36321 GeneCards: TIMP1 Gene | ||||||||||
|
|||||||||||
| RNA expression pattern | |||||||||||
 |
|||||||||||
| More reference expression data | |||||||||||
| Orthologs | |||||||||||
| Species | Human | Mouse | |||||||||
| Entrez | 7076 | 21857 | |||||||||
| Ensembl | ENSG00000102265 | ENSMUSG00000001131 | |||||||||
| UniProt | P01033 | P12032 | |||||||||
| RefSeq (mRNA) | NM_003254 | NM_001044384 | |||||||||
| RefSeq (protein) | NP_003245 | NP_001037849 | |||||||||
| Location (UCSC) | Chr X: 47.44 – 47.45 Mb |
Chr X: 20.87 – 20.87 Mb |
|||||||||
| PubMed search | [1] | [2] | |||||||||
This protein a member of the TIMP family. The glycoprotein is a natural inhibitor of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function.
==============
PRKCA see PRKCG
Here Phorbol esters, diacylglycerol, and calcium become important for the cell performance of various functions. Did I mention few targets, I truly believe I did!
CDH1 The Cadherin by excellence, not only important as adhesion molecule and role in metastasis. Its role is amplified by what else anchors here such as Vinculin, and others molecules such as Plakoglobins, amplifying the role. Remember even Cytochrome C is anchored at the mitochondrial membrane and its release leads to apoptosis!
The anchors are legitimate targets therefore, and brings to mind NACA1 in the anchoring to Histone deacetyl transferase (SEE OUR LEUKEMIA SECTION) CDH13 THAT'S ANOTHER BALL GAME ALL TOGETHER. THE CELL TWEACKS SOMETHING AND IT IS ANOTHER BALL GAME ALL TOGETHER!
==========================
NOMENCLATURE (II) ON SOME GENES REPORTED IN PANCREATIC CANCER
SMAD4:
Co-factor of TGF Beta, involved in Juvenile Polyposis syndrome,
mutations lead to a form of dwarfism and pulmonary hypertension
S100-P; important for cell differentiation and progression, through the EZRIN, it participates in lighting PI3K pathway. It also participates in propagation of Osteosarcoma.
NFAT: Uses calmodulin-calcineurin pathways to drive to specific transcription factors for growth and invasion particularly in breast cancer. It the site of action of Cyclosporine as its disturbance mislocates immune modulating cyclins and growth factors. NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion.
PRKCG: reminds us that the pancreas is heavily full of nerves. Whether this is the origin of pains from the pancreatic cancer is a question, but through PICK1, it links this to mitochondrial function/membrane.
Remember the role of Mitochondria, pancreas and glycolysis, this connection to the mitochondria raises questions in all kind of directions, further investigation is needed here... " be involved in neuropathic pain development. Defects in this protein have been associated with neurodegenerative disorder spinocerebellar ataxia-14 (SCA14).[3]" (wikipedia)
MLL3: binds to the Core Binding factor like molecule for blood and neuron differentiation. T
his CBF contains Retinoblastoma protein 5 therefore interfere with a stop in cell division
but also involve THIS!
Nuclear receptor coactivator 6 is a protein that in humans is encoded by the NCOA6 gene.[1][2][3]
The protein encoded by this gene is a transcriptional coactivator that can interact with nuclear hormone receptors to enhance their transcriptional activator functions. The encoded protein has been shown to be involved in the hormone-dependent coactivation of several receptors, including prostanoid, retinoid, vitamin D3, thyroid hormone, and steroid receptors. The encoded protein may also act as a general coactivator since it has been shown to interact with some basal transcription factors, histone acetyltransferases, and methyltransferases.[3]"
Making MLL3 a huge target! although disruptions here may have implication on all cells.
S100-P; important for cell differentiation and progression, through the EZRIN, it participates in lighting PI3K pathway. It also participates in propagation of Osteosarcoma.
NFAT: Uses calmodulin-calcineurin pathways to drive to specific transcription factors for growth and invasion particularly in breast cancer. It the site of action of Cyclosporine as its disturbance mislocates immune modulating cyclins and growth factors. NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion.
PRKCG: reminds us that the pancreas is heavily full of nerves. Whether this is the origin of pains from the pancreatic cancer is a question, but through PICK1, it links this to mitochondrial function/membrane.
Remember the role of Mitochondria, pancreas and glycolysis, this connection to the mitochondria raises questions in all kind of directions, further investigation is needed here... " be involved in neuropathic pain development. Defects in this protein have been associated with neurodegenerative disorder spinocerebellar ataxia-14 (SCA14).[3]" (wikipedia)
MLL3: binds to the Core Binding factor like molecule for blood and neuron differentiation. T
his CBF contains Retinoblastoma protein 5 therefore interfere with a stop in cell division
but also involve THIS!
NCOA6
From Wikipedia, the free encyclopedia
| Nuclear receptor coactivator 6 | |||||
|---|---|---|---|---|---|
| Identifiers | |||||
| Symbols | NCOA6; AIB3; ASC2; NRC; PRIP; RAP250; TRBP | ||||
| External IDs | OMIM: 605299 MGI: 1929915 HomoloGene: 40920 GeneCards: NCOA6 Gene | ||||
|
|||||
| RNA expression pattern | |||||
 |
|||||
| More reference expression data | |||||
| Orthologs | |||||
| Species | Human | Mouse | |||
| Entrez | 23054 | 56406 | |||
| Ensembl | ENSG00000198646 | ENSMUSG00000038369 | |||
| UniProt | Q14686 | A2AQM9 | |||
| RefSeq (mRNA) | NM_001242539 | NM_001242558 | |||
| RefSeq (protein) | NP_001229468 | NP_001229487 | |||
| Location (UCSC) | Chr 20: 33.28 – 33.41 Mb |
Chr 2: 155.39 – 155.47 Mb |
|||
| PubMed search | [1] | [2] | |||
The protein encoded by this gene is a transcriptional coactivator that can interact with nuclear hormone receptors to enhance their transcriptional activator functions. The encoded protein has been shown to be involved in the hormone-dependent coactivation of several receptors, including prostanoid, retinoid, vitamin D3, thyroid hormone, and steroid receptors. The encoded protein may also act as a general coactivator since it has been shown to interact with some basal transcription factors, histone acetyltransferases, and methyltransferases.[3]"
Making MLL3 a huge target! although disruptions here may have implication on all cells.
Saturday, March 16, 2013
THE AURORA KINASES
ONCE AGAIN YOU SEE HOW THE CELL PLAYS, USING SIMPLE THINGS THAT GET COMPLICATED REALLY QUICKLY!
Given our current understanding of the way they are suppressed by normal activity of P53, the aurora Kinase inhibitors should be used in cancers where P53 is clearly dys-regulated, and probably in disease with positive Prostate Stem Cell Antigen. This open the door to Sarcomas (chondrosarcoma being the most cited) and Pancreatic cancers (as well as Bladder cancers).
GADD45, a P53 dependent protein that inhibits Cdc2/Cyclin B1 could therefore be the best predictor of Aurora activity.
Quantification of CDCA8/Borealin, BIRC5/survivin, and INCENP may provide additional information on AURORA KINASE ACTIVITY. Like the core Binding Factor, these 3 Molecules form the Chromosomal Passenger Complex (CPC) which interact with POGZ, EVI5, and JTB.
Niehrs at al further define the role of GADD45 as "Gadd45 recruits nucleotide and/or base excision repair factors to gene-specific loci and acts as an adapter between repair factors and chromatin, thereby creating a nexus between epigenetics and DNA repair." Therefore explaining how P53 induced arrest is followed by DNA repair through recruitment of GADD45. When the cell is trying to repair itself with increase in GADD45, of course it wont want to die, therefore over-expression of GADD45 decrease the c-JUN, protecting therefore from TNF induced apoptosis. GADD45 is not good theoretically when you use Cisplatin or radiation for that matter!
*POGZ explains Nuclear transposition of P53 effects as it impacts SP1, a transcription factor with inteaction of all major playors in the cell including E2F1, POU2F1. YOU TARGET SP1 WITH WITH AFERIN FOR EXAMPLE, IT IS IMPOSSIBLE TO COME UP EMPTY HANDED.
*EVI5
"Identification of Rab11 as a small GTPase binding protein for the Evi5 oncogene"
Protein JTB also known as the jumping translocation breakpoint protein or prostate androgen-regulated protein (PAR) is a protein that in humans is encoded by the JTB gene.[1][2]
The JTB family of proteins contains several jumping translocation breakpoint proteins or JTBs. Jumping translocation (JT) is an unbalanced translocation that comprises amplified chromosomal segments jumping to various telomeres. JTB has been found to fuse with the telomeric repeats of acceptor telomeres in a case of JT. Homo sapiens JTB (hJTB) encodes a transmembrane protein that is highly conserved among divergent eukaryotic species. JT results in a hJTB truncation, which potentially produces an hJTB product devoid of the transmembrane domain. hJTB is located in a gene-rich region at 1q21, called EDC (Epidermal Differentiation Complex).[1] JTB has also been implicated in prostatic carcinomas.[3]
KANOME ET AL SUGGESTED
"JTB-induced clustering of mitochondria around the nuclear periphery and swelling of each mitochondrion. In those mitochondria, membrane potential, as monitored with a JC-1 probe, was significantly reduced. Coinciding with these changes in mitochondria, JTB retarded the growth of the cells and conferred resistance to TGF-
1-induced
apoptosis. These activities were dependent on the N-terminal processing
and induced by wild-type JTB but not by a mutant resistant to cleavage.
These findings raised the possibility that aberration of JTB in
structure or expression induced neoplastic changes in cells through
dysfunction of mitochondria leading to deregulated cell growth and/or
death."
==================================================================
ONCE AGAIN YOU SEE HOW THE CELL PLAYS, USING SIMPLE THINGS THAT GET COMPLICATED REALLY QUICK!
Given our current understanding of the way they are suppressed by normal activity of P53, the aurora Kinase inhibitors should be used in cancers where P53 is clearly dys-regulated, and probably in disease with positive Prostate Stem Cell Antigen. This open the door to Sarcomas (chondrosarcoma being the most cited) and Pancreatic cancers (as well as Bladder cancers).
GADD45, a P53 dependent protein that inhibits Cdc2/Cyclin B1 could therefore be the best predictor of Aurora activity.
Quantification of CDCA8/Borealin, BIRC5/survivin, and INCENP may provide additional information on AURORA KINASE ACTIVITY. Like the core Binding Factor, these 3 Molecules form the Chromosomal Passenger Complex (CPC) which interact with POGZ, EVI5, and JTB.
Niehrs at al further define the role of GADD45 as "Gadd45 recruits nucleotide and/or base excision repair factors to gene-specific loci and acts as an adapter between repair factors and chromatin, thereby creating a nexus between epigenetics and DNA repair." Therefore explaining how P53 induced arrest is followed by DNA repair through recruitment of GADD45. When the cell is trying to repair itself with increase in GADD45, of course it wont want to die, therefore over-expression of GADD45 decrease the c-JUN, protecting therefore from TNF induced apoptosis. GADD45 is not good theoretically when you use Cisplatin or radiation for that matter!
*POGZ explains Nuclear transposition of P53 effects as it impacts SP1, a transcription factor with inteaction of all major playors in the cell including E2F1, POU2F1. YOU TARGET SP1 WITH WITH AFERIN FOR EXAMPLE, IT IS IMPOSSIBLE TO COME UP EMPTY HANDED.
*EVI5
"Identification of Rab11 as a small GTPase binding protein for the Evi5 oncogene"
This article has been cited by other articles in PMC.
Abstract
The Evi5 oncogene has recently been shown to regulate the stability and accumulation of critical G1
cell cycle factors including Emi1, an inhibitor of the
anaphase-promoting complex/cyclosome, and cyclin A. Sequence analysis of
the amino terminus of Evi5 reveals a Tre-2, Bub2, Cdc16 domain, which
has been shown to be a binding partner and GTPase-activating protein
domain for the Rab family of small Ras-like GTPases. Here we describe
the identification of Evi5 as a candidate binding protein for Rab11, a
GTPase that regulates intracellular transport and has specific roles in
endosome recycling and cytokinesis. By yeast two-hybrid analysis,
immunoprecipitation, and Biacore analysis, we demonstrate that Evi5
binds Rab11a and Rab11b in a GTP-dependent manner. However, Evi5
displays no activation of Rab11 GTPase activity in vitro. Evi5 colocalizes with Rab11 in vivo,
and overexpression of Rab11 perturbs the localization of Evi5,
redistributing it into Rab11-positive recycling endosomes.
Interestingly, in vitro binding studies show that Rab11
effector proteins including FIP3 compete with Evi5 for binding to Rab11,
suggesting a partitioning between Rab11–Evi5 and Rab11 effector
complexes. Indeed, ablation of Evi5 by RNA interference causes a
mislocalization of FIP3 at the abscission site during cytokinesis. These
data demonstrate that Evi5 is a Rab11 binding protein and that Evi5 may
cooperate with Rab11 to coordinate vesicular trafficking, cytokinesis,
and cell cycle control independent of GTPase-activating protein
function.
Keywords: cytokinesis, GTPase-activating protein, recycling endosome".
*JTB
JTB (gene)
From Wikipedia, the free encyclopedia
| Jumping translocation breakpoint | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
|
|||||||||||
| Identifiers | |||||||||||
| Symbols | JTB; HJTB; HSPC222; PAR; hJT | ||||||||||
| External IDs | OMIM: 604671 MGI: 1346082 HomoloGene: 4870 GeneCards: JTB Gene | ||||||||||
|
|||||||||||
| RNA expression pattern | |||||||||||
 |
|||||||||||
 |
|||||||||||
| More reference expression data | |||||||||||
| Orthologs | |||||||||||
| Species | Human | Mouse | |||||||||
| Entrez | 10899 | 23922 | |||||||||
| Ensembl | ENSG00000143543 | ENSMUSG00000027937 | |||||||||
| UniProt | O76095 | O88824 | |||||||||
| RefSeq (mRNA) | NM_006694 | NM_206924 | |||||||||
| RefSeq (protein) | NP_006685 | NP_996807 | |||||||||
| Location (UCSC) | Chr 1: 153.95 – 153.95 Mb |
Chr 3: 90.23 – 90.24 Mb |
|||||||||
| PubMed search | [1] | [2] | |||||||||
| Jumping translocation breakpoint protein (JTB) | |||
|---|---|---|---|
| Identifiers | |||
| Symbol | JTB | ||
| Pfam | PF05439 | ||
| InterPro | IPR008657 | ||
|
|||
The JTB family of proteins contains several jumping translocation breakpoint proteins or JTBs. Jumping translocation (JT) is an unbalanced translocation that comprises amplified chromosomal segments jumping to various telomeres. JTB has been found to fuse with the telomeric repeats of acceptor telomeres in a case of JT. Homo sapiens JTB (hJTB) encodes a transmembrane protein that is highly conserved among divergent eukaryotic species. JT results in a hJTB truncation, which potentially produces an hJTB product devoid of the transmembrane domain. hJTB is located in a gene-rich region at 1q21, called EDC (Epidermal Differentiation Complex).[1] JTB has also been implicated in prostatic carcinomas.[3]
KANOME ET AL SUGGESTED
"JTB-induced clustering of mitochondria around the nuclear periphery and swelling of each mitochondrion. In those mitochondria, membrane potential, as monitored with a JC-1 probe, was significantly reduced. Coinciding with these changes in mitochondria, JTB retarded the growth of the cells and conferred resistance to TGF-
1-induced
apoptosis. These activities were dependent on the N-terminal processing
and induced by wild-type JTB but not by a mutant resistant to cleavage.
These findings raised the possibility that aberration of JTB in
structure or expression induced neoplastic changes in cells through
dysfunction of mitochondria leading to deregulated cell growth and/or
death."==================================================================
ONCE AGAIN YOU SEE HOW THE CELL PLAYS, USING SIMPLE THINGS THAT GET COMPLICATED REALLY QUICK!
GENES MUTATED AT CHROMOSOME 8q IN PANCREATIC CANCER
1.CDH 17
The change in expression of this gene in advance pancreatic cancer does not come as a surprise
because by now we have become familiar with the fact that advance cancer is on the move and should metastasize, CDH belong to the Cadherin family, the family of adhesion molecule, cells need to detach and go. Takamura M et al. have shown that the Liver-intestine Cadherins reduction correlated with Colon cancer metastatic to lymph nodes.
CDH17 appears to be a gene of differentiation and could help determine the origin of of tissue in those ambivalent cases where we are dealing with an cancer of unknown primary. It is a proton pump dependent cellular membrane structure. What is fascinating is the fact that how quickly these structures are internalized or their stimulation effect is transmitted to the Nucleus at splicing center to be expressed as differentiation agents.
Zhu at al. have suggested that the hepatic Nuclear factor 1 and CDX2 participate in the regulation of CDH17 expression. (larger speculation Where is the p molecule counterpart? since this cadherin is on 8q)
2. PSCA: PROSTATE stem cell Antigen
When the prostate lends a hand to the pancreas you know this is bad news. This antigen does not exist in the normal pancreas. But when it appears in the Pancreas you know the disease is advanced. Even in the Prostate the amplification of this antigen marks very high Gleason at presentation or bone Metastatasis. It is not PSA we should be looking for, but PCR overexpression of PSCA. By its name it says it all "Stem cell" meaning the cancer is now OMNIPOTENT and Incredibly resistant. The presence of this antigen is not only predictive but also prognosis. The makers of SIPULEUCEL-T should be incubating patient dendritic cells with with this antigen rather than PAP to be active in pancreatic cancers.
One interesting observation was made by Moore et al. while they were knocking down rats to further study this gene, they noted an over-expression of the AURORA kinases, these genes that regulate mitosis by controlling events at the Centrosomes. It is interesting because it raises the possibility of using the PSCA as an indicator for use of Aurora inhibitors (Hesperadin, ZM447439,Tozasertib,VX680). Also recent evidence of activity of Abraxane in Pancreatic cancer would open up the opportunity to use Abraxane in combination with Aurora kinase inhibitor in this disease. Clearly if P53 is dysregulated, we can safely assume the Aurora kinase may have a role since they are more likely over-expressed.
SO: new target Therapy in Pancreatic cancer ABRAXANE with an Aurora MutiKinase Inhibitor would be the next step if we want to introduce target therapy in Pancreatic cancers.
A recent TV documentary showed that a chemical compound that the EPA is investigating because it has contaminated the drinking waters in the USA caused cells to have Multiple Centrosomes in exposed cells, clearly is it affecting the AURORA and most likely AURORA A. It raised the possibility that Metallic based chemical compound toxicity may have a larger weight on this pathways. I wonder what Arsenic Trioxyde would add to this! remember the anti-Aurora have a secondary anti-Histone (3) activity contributing to their effect in CML.
3. MYC:
*a GLOBAL AMPLIFIER OF ALL GENES INCLUDING PROLIFERATIVE GENES.
*RECRUITER OF HISTONES DEACETYLASE PROTEIN
*OVERACTION OF CBF LIKE MOLECULES
*IT HAS IRES THE INTERNAL RIBOSOME ENTRY SITES WHICH IS THE KEY TO THE DOOR TO RIBOSOME FOR PROTEIN FORMATION (REGULATOR FOR MATION) AND HAS A THE ZIPPER TO ATTACH AND OPEN WIDE DNA FOR TRANSLATION. OVER-EXPRESSION OF MYC DRIVES PROLIFERATION AT HIGH PACE!
WIKIPEDIA SAYS IT ALL
Myc protein is a transcription factor that activates expression of many genes through binding on consensus sequences (Enhancer Box sequences (E-boxes)) and recruiting histone acetyltransferases (HATs). It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 co-activator, it inhibits expression of Miz-1 target genes. In addition, myc has a direct role in the control of DNA replication.[4]
Myc is activated upon various mitogenic signals such as Wnt, Shh and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects. The first to be discovered was its capability to drive cell proliferation (upregulates cyclins, downregulates p21), but it also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2), differentiation and stem cell self-renewal. Myc is a very strong proto-oncogene and it is very often found to be upregulated in many types of cancers. Myc overexpression stimulates gene amplification,[5] presumably through DNA over-replication."
"
The change in expression of this gene in advance pancreatic cancer does not come as a surprise
because by now we have become familiar with the fact that advance cancer is on the move and should metastasize, CDH belong to the Cadherin family, the family of adhesion molecule, cells need to detach and go. Takamura M et al. have shown that the Liver-intestine Cadherins reduction correlated with Colon cancer metastatic to lymph nodes.
CDH17 appears to be a gene of differentiation and could help determine the origin of of tissue in those ambivalent cases where we are dealing with an cancer of unknown primary. It is a proton pump dependent cellular membrane structure. What is fascinating is the fact that how quickly these structures are internalized or their stimulation effect is transmitted to the Nucleus at splicing center to be expressed as differentiation agents.
Zhu at al. have suggested that the hepatic Nuclear factor 1 and CDX2 participate in the regulation of CDH17 expression. (larger speculation Where is the p molecule counterpart? since this cadherin is on 8q)
2. PSCA: PROSTATE stem cell Antigen
When the prostate lends a hand to the pancreas you know this is bad news. This antigen does not exist in the normal pancreas. But when it appears in the Pancreas you know the disease is advanced. Even in the Prostate the amplification of this antigen marks very high Gleason at presentation or bone Metastatasis. It is not PSA we should be looking for, but PCR overexpression of PSCA. By its name it says it all "Stem cell" meaning the cancer is now OMNIPOTENT and Incredibly resistant. The presence of this antigen is not only predictive but also prognosis. The makers of SIPULEUCEL-T should be incubating patient dendritic cells with with this antigen rather than PAP to be active in pancreatic cancers.
One interesting observation was made by Moore et al. while they were knocking down rats to further study this gene, they noted an over-expression of the AURORA kinases, these genes that regulate mitosis by controlling events at the Centrosomes. It is interesting because it raises the possibility of using the PSCA as an indicator for use of Aurora inhibitors (Hesperadin, ZM447439,Tozasertib,VX680). Also recent evidence of activity of Abraxane in Pancreatic cancer would open up the opportunity to use Abraxane in combination with Aurora kinase inhibitor in this disease. Clearly if P53 is dysregulated, we can safely assume the Aurora kinase may have a role since they are more likely over-expressed.
SO: new target Therapy in Pancreatic cancer ABRAXANE with an Aurora MutiKinase Inhibitor would be the next step if we want to introduce target therapy in Pancreatic cancers.
A recent TV documentary showed that a chemical compound that the EPA is investigating because it has contaminated the drinking waters in the USA caused cells to have Multiple Centrosomes in exposed cells, clearly is it affecting the AURORA and most likely AURORA A. It raised the possibility that Metallic based chemical compound toxicity may have a larger weight on this pathways. I wonder what Arsenic Trioxyde would add to this! remember the anti-Aurora have a secondary anti-Histone (3) activity contributing to their effect in CML.
3. MYC:
*a GLOBAL AMPLIFIER OF ALL GENES INCLUDING PROLIFERATIVE GENES.
*RECRUITER OF HISTONES DEACETYLASE PROTEIN
*OVERACTION OF CBF LIKE MOLECULES
*IT HAS IRES THE INTERNAL RIBOSOME ENTRY SITES WHICH IS THE KEY TO THE DOOR TO RIBOSOME FOR PROTEIN FORMATION (REGULATOR FOR MATION) AND HAS A THE ZIPPER TO ATTACH AND OPEN WIDE DNA FOR TRANSLATION. OVER-EXPRESSION OF MYC DRIVES PROLIFERATION AT HIGH PACE!
WIKIPEDIA SAYS IT ALL
Myc protein is a transcription factor that activates expression of many genes through binding on consensus sequences (Enhancer Box sequences (E-boxes)) and recruiting histone acetyltransferases (HATs). It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 co-activator, it inhibits expression of Miz-1 target genes. In addition, myc has a direct role in the control of DNA replication.[4]
Myc is activated upon various mitogenic signals such as Wnt, Shh and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects. The first to be discovered was its capability to drive cell proliferation (upregulates cyclins, downregulates p21), but it also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2), differentiation and stem cell self-renewal. Myc is a very strong proto-oncogene and it is very often found to be upregulated in many types of cancers. Myc overexpression stimulates gene amplification,[5] presumably through DNA over-replication."
"
PROOF OF CONCEPTS: THE CASE OF PANCREATIC CANCER
1. "P" ARM VERSUS "Q"
-----------------------------
As you look at the location of Genes, one will quickly notice that various genes have their family counterpart not close on the same chromosome. But instead on a different chromosome altogether. In general we almost treat this information in a profane manner in that we overlook the meaning of this. Nature, however, has no place for randomness. Everything has deep meaning and NUANCES OR MINIMAL VARIATIONS can make a world of difference. Should you doubt this statement, ask the people with Sickle cell, they are not laughing about that nuance in Hemoglobins. So when a family member has put in a different chromosome, there is no pun intended.
ERBB1 is on chromosome 7p12 (involved in Glioblastoma and Squamous cell head and neck cancers)
ERBB2 is on chromosome 17q11.2-q12 (involved in breast, Ovarian and cervical cancer)
Also however, we note that the family member is put on a "p" rather than "q" location. This also has a profound meaning. It just turn out that mutation on "q" location seems to have the worse prognosis and are more likely to be expressed than those on "p" location.
The bad guy MYC is located 8q24 and is found on advanced forms of cancers (Ovarian, Breast, small cell, Esophageal and cervical but also in the Burkitt (ALL))
The nice MYCN, often a better prognosis indicator, is located on 2p24 but still can be involved in Neurobalstoma.
These are in fact speculation but check it out!
Another example
just go ahead and compare
breast cancer with FGFR1 located 8p11
and breast cancer with EGFR1 located 10q25
and call me if you find different!
PROOF OF CONCEPT NEEDED FOR PANCREATIC CANCER:
One of the complication or hurdle you encounter when you are dealing with abnormal genes
in pancreatic cancers is the the genes found in abnormal cancers are also found in benign conditions such as Adenoma or even pancreatitis. Now if we assume that this is an Adenocarcinoma of the same origin embryonically as the colon (check that assumption out), we could apply the colon cancer model where
EARLY CANCER FOR ADENOCARCINOMA IS ANNOUNCED BY LOSS OR MUTATION IN CHROMOSOME 17: IE GENES (FOLLOWING THE COLON MODEL)
-----------------------------------
-KRT20
-TEM 7
-MAP2K4
BAT-26
ALOX 12
TP53
BIRC5
NME1
ERBB2
GAS
TM4SF5
LATE CANCER, LOSS OF CHROMOSOME 8 (FOLLOWING THE COLON MODEL)
CDH4
PSCA
MYC
(FGFR1 AND BAG4 ARE HAVE A "p" LOCATION ON THE CHROMOSOSME)
-----------------------------
As you look at the location of Genes, one will quickly notice that various genes have their family counterpart not close on the same chromosome. But instead on a different chromosome altogether. In general we almost treat this information in a profane manner in that we overlook the meaning of this. Nature, however, has no place for randomness. Everything has deep meaning and NUANCES OR MINIMAL VARIATIONS can make a world of difference. Should you doubt this statement, ask the people with Sickle cell, they are not laughing about that nuance in Hemoglobins. So when a family member has put in a different chromosome, there is no pun intended.
ERBB1 is on chromosome 7p12 (involved in Glioblastoma and Squamous cell head and neck cancers)
ERBB2 is on chromosome 17q11.2-q12 (involved in breast, Ovarian and cervical cancer)
Also however, we note that the family member is put on a "p" rather than "q" location. This also has a profound meaning. It just turn out that mutation on "q" location seems to have the worse prognosis and are more likely to be expressed than those on "p" location.
The bad guy MYC is located 8q24 and is found on advanced forms of cancers (Ovarian, Breast, small cell, Esophageal and cervical but also in the Burkitt (ALL))
The nice MYCN, often a better prognosis indicator, is located on 2p24 but still can be involved in Neurobalstoma.
These are in fact speculation but check it out!
Another example
just go ahead and compare
breast cancer with FGFR1 located 8p11
and breast cancer with EGFR1 located 10q25
and call me if you find different!
PROOF OF CONCEPT NEEDED FOR PANCREATIC CANCER:
One of the complication or hurdle you encounter when you are dealing with abnormal genes
in pancreatic cancers is the the genes found in abnormal cancers are also found in benign conditions such as Adenoma or even pancreatitis. Now if we assume that this is an Adenocarcinoma of the same origin embryonically as the colon (check that assumption out), we could apply the colon cancer model where
EARLY CANCER FOR ADENOCARCINOMA IS ANNOUNCED BY LOSS OR MUTATION IN CHROMOSOME 17: IE GENES (FOLLOWING THE COLON MODEL)
-----------------------------------
-KRT20
-TEM 7
-MAP2K4
BAT-26
ALOX 12
TP53
BIRC5
NME1
ERBB2
GAS
TM4SF5
LATE CANCER, LOSS OF CHROMOSOME 8 (FOLLOWING THE COLON MODEL)
CDH4
PSCA
MYC
(FGFR1 AND BAG4 ARE HAVE A "p" LOCATION ON THE CHROMOSOSME)
Friday, March 15, 2013
NOMENCLATURE ON SOME GENES REPORTED IN PANCREATIC CANCER
SMAD4: Co-factor of TGF Beta, involved in Juvenile Polyposis syndrome, mutation lead to a form of dwarfism and pulmonary hypertension
S100-P; important for cell differentiation and progression, through the EZRIN, it participate in lighting PI3K pathway. It also participate in propagation of Osteosarcoma
NFAT: Uses calmodulin-calcineurin pathways to drive to specific transcription factors for growth and invasion particularly in breast cancer. It the site of action of Cyclosporine as it disturbance mislocate immune modulating cyclins and growth factors. NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion.
PRKCG: remind us that the pancreas is heavily full of nerve. whether this is the origin of pains from the pancreatic cancer is a question, but through PICK1, it links this to mitochondrial function/membrane
remember the role of Mitochondria, pancreas and glucolysis, this connection to the mitochondria raises questions in all kind of directions, further investigation is needed here... " be involved in neuropathic pain development. Defects in this protein have been associated with neurodegenerative disorder spinocerebellar ataxia-14 (SCA14).[3]" (wikipedia)
MLL3: binds to the Core Binding factor like molecule for blood and neuron differentiation. T
his CBF contain Retinoblastoma protein 5 therefore interfere with a stop in cell division
but also involve THIS!
Nuclear receptor coactivator 6 is a protein that in humans is encoded by the NCOA6 gene.[1][2][3]
The protein encoded by this gene is a transcriptional coactivator that can interact with nuclear hormone receptors to enhance their transcriptional activator functions. The encoded protein has been shown to be involved in the hormone-dependent coactivation of several receptors, including prostanoid, retinoid, vitamin D3, thyroid hormone, and steroid receptors. The encoded protein may also act as a general coactivator since it has been shown to interact with some basal transcription factors, histone acetyltransferases, and methyltransferases.[3]"
Making MLL3 a huge target! although disruptions here may have implication on all cells.
BETA 4 INTEGRIN: a gene that does more than being an adhesion molecules
it is the road to a poorly described and not well recognized pathway
Not only it gives Hypertrophy but epidermolysis goes through this intergrin, it participates in the ERBB pathways. Mark my word this is are critical pathways in pancreatic cancers.
MTIF GIVES YOU MOTIVES TO AFTER IT!
MAKING THE ERBIN A PLAUSIBLE TARGET.
MAKING ALSO A STRONGER CASE THAT MEMBRANE CYTOSKELETON SHOULD BE A GOOD TARGET BECAUSE OF THE WAY IT DRIVES ITS PATHWAY NOT THROUGH THE CYTOSOL( ALTHOUGH THERE IS A SECONDARY RAS/MAPK STIMULATION,) BUT THE PATHWAY HERE IS THROUGH THE RETICULUM ENDOTHELIUM DIRECTLY TO THE NUCLEUS! CONCEPTUALLY, AN ANTIBODY TO LAMININ ATTACHED TO A SUBUNIT OF A LIPOLYTIC COMPOUND SHOULS HAVE AN THERAPEUTIC OR CHEMICAL EFFECT AT THIS LEVEL. AN INTERESTING APPROACH. CHANCES ARE IT MAY ALSO HAVE A STRONG IMPACT ON THE WNT-PATHWAY WHICH TRAVEL CLOSE BY AND IS IMPORTANT IN BREAST CANCER!
MTA-1: THIS IS A REAL OPPORTUNITY
Here the cell stopped fooling around trying to lie to you. Here the cell says to you this is one of my way to metastatasize. yes this is my gene to mestastasize and I will work like any CBF like molecule by attaching to DNA and make me protein that will have me spread like wild fire! And by the way I will use a growth hormone like Estrogen. no kidding around
"MTA1 has been shown to interact with HDAC1,[4][5] Histone deacetylase 2,[4][6][5] MTA2,[4] Estrogen receptor alpha[7][5] and MNAT1.[8] MTA1 has also been shown to inhibit SMAD7 at the transcriptional level[9]"
IT DOES NEED TGF TO WORK, TGF IS FOR LOCAL GROWTH ANYWAY THAT WHY IT BLOCKS THE SMAD.
SPINT2
Mutation at SPINT2 leads to significant Malignant Ascites and peritoneal invasion, SPINT 2 is a suppressor of this phenomena. On the Intestinal membrane deficiency of SPINT2 leads to sodium induced/containing diarrhea. This is also true in Ovarian cancer or peritoneal based tumors. Targeting this is better then trying Avastin, a blind approach when it comes to effusions management.
MMP11
A metalloproteiase, aimed at breaking down extracellular matrix and be on the move. Targeting MMP for cancer has proven futile. The cell is not stupid, it does not put out things that is going to hunt it! It build first a strong inhibitor to metalloproteiases. In fact lack of inhibitors has been recognized as the main pathogenesis of TTP. With the ADAMs being the integrins involved! and next is that Inhibitor which is of course expressed in pancreatic cancer.
TIMP1
TIMP metallopeptidase inhibitor 1, also known as TIMP1, a tissue inhibitor of metalloproteinases, is a glycoprotein that is expressed from the several tissues of organisms.
This protein a member of the TIMP family. The glycoprotein is a natural inhibitor of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function.
==============
PRKCA see PRKCG
Here Phorbol esters, diacylglycerol, and calcium become important for the cell performance of various functions. Did I mention few targets, I truly believe I did!
CDH1 The Cadherin by excellence, not only important as adhesion molecule and role in metastasis. Its role is amplified by what else anchors here such as Vinculin, and others molecules such as Plakoglobins, amplifying the role. Remember even Cytochrome C is anchored at the mitochondrial membrane and its release leads to apoptosis!
The anchors are legitimate targets therefore, and brings to mind NACA1 in the anchoring to Histone deacetyl transferase (SEE OUR LEUKEMIA SECTION) CDH13 THAT'S ANOTHER BALL GAME ALL TOGETHER. THE CELL TWEACKS SOMETHING AND IT IS ANOTHER BALL GAME ALL TOGETHER!
==========================
ALOX5AP
ACVR1B
PCD1
IRS2
TJP1
MADH6
S100-P; important for cell differentiation and progression, through the EZRIN, it participate in lighting PI3K pathway. It also participate in propagation of Osteosarcoma
NFAT: Uses calmodulin-calcineurin pathways to drive to specific transcription factors for growth and invasion particularly in breast cancer. It the site of action of Cyclosporine as it disturbance mislocate immune modulating cyclins and growth factors. NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion.
PRKCG: remind us that the pancreas is heavily full of nerve. whether this is the origin of pains from the pancreatic cancer is a question, but through PICK1, it links this to mitochondrial function/membrane
remember the role of Mitochondria, pancreas and glucolysis, this connection to the mitochondria raises questions in all kind of directions, further investigation is needed here... " be involved in neuropathic pain development. Defects in this protein have been associated with neurodegenerative disorder spinocerebellar ataxia-14 (SCA14).[3]" (wikipedia)
MLL3: binds to the Core Binding factor like molecule for blood and neuron differentiation. T
his CBF contain Retinoblastoma protein 5 therefore interfere with a stop in cell division
but also involve THIS!
NCOA6
From Wikipedia, the free encyclopedia
| Nuclear receptor coactivator 6 | |||||
|---|---|---|---|---|---|
| Identifiers | |||||
| Symbols | NCOA6; AIB3; ASC2; NRC; PRIP; RAP250; TRBP | ||||
| External IDs | OMIM: 605299 MGI: 1929915 HomoloGene: 40920 GeneCards: NCOA6 Gene | ||||
|
|||||
| RNA expression pattern | |||||
|
|||||
| More reference expression data | |||||
| Orthologs | |||||
| Species | Human | Mouse | |||
| Entrez | 23054 | 56406 | |||
| Ensembl | ENSG00000198646 | ENSMUSG00000038369 | |||
| UniProt | Q14686 | A2AQM9 | |||
| RefSeq (mRNA) | NM_001242539 | NM_001242558 | |||
| RefSeq (protein) | NP_001229468 | NP_001229487 | |||
| Location (UCSC) | Chr 20: 33.28 – 33.41 Mb |
Chr 2: 155.39 – 155.47 Mb |
|||
| PubMed search | [1] | [2] | |||
The protein encoded by this gene is a transcriptional coactivator that can interact with nuclear hormone receptors to enhance their transcriptional activator functions. The encoded protein has been shown to be involved in the hormone-dependent coactivation of several receptors, including prostanoid, retinoid, vitamin D3, thyroid hormone, and steroid receptors. The encoded protein may also act as a general coactivator since it has been shown to interact with some basal transcription factors, histone acetyltransferases, and methyltransferases.[3]"
Making MLL3 a huge target! although disruptions here may have implication on all cells.
BETA 4 INTEGRIN: a gene that does more than being an adhesion molecules
it is the road to a poorly described and not well recognized pathway
The LysRS-Ap4A-MITF signaling pathway
The LysRS-Ap4A-MITF signaling pathway was first discovered in mast cells, in which , the MAPK pathway is activated upon allergen stimulation. Lysyl-tRNA synthetase (LysRS), which normally resides in the multisynthetase complex with other tRNA sythetases, is phosphorylated on Serine 207 in a MAPK-dependent manner.[30] This phosphorylation causes LysRS to change its conformation, detach from the complex and translocate into the nucleus, where it associates with the MITF-HINT1 inhibitory complex. The conformational change switches LysRS activity from aminoacylation of Lysine tRNA to diadenosine tetraphosphate (Ap4A) production. Ap4A binds to HINT1, which releases MITF from the inhibitory complex, allowing it to transcribe its target genes.[31] Activation of the LysRS-Ap4A-MITF signaling pathway by isoproterenol has been confirmed in cardiomyocytes, where MITF is a major regulator of cardiac growth and hypertrophy.[32][33](wikipedia)Not only it gives Hypertrophy but epidermolysis goes through this intergrin, it participates in the ERBB pathways. Mark my word this is are critical pathways in pancreatic cancers.
MTIF GIVES YOU MOTIVES TO AFTER IT!
MAKING THE ERBIN A PLAUSIBLE TARGET.
MAKING ALSO A STRONGER CASE THAT MEMBRANE CYTOSKELETON SHOULD BE A GOOD TARGET BECAUSE OF THE WAY IT DRIVES ITS PATHWAY NOT THROUGH THE CYTOSOL( ALTHOUGH THERE IS A SECONDARY RAS/MAPK STIMULATION,) BUT THE PATHWAY HERE IS THROUGH THE RETICULUM ENDOTHELIUM DIRECTLY TO THE NUCLEUS! CONCEPTUALLY, AN ANTIBODY TO LAMININ ATTACHED TO A SUBUNIT OF A LIPOLYTIC COMPOUND SHOULS HAVE AN THERAPEUTIC OR CHEMICAL EFFECT AT THIS LEVEL. AN INTERESTING APPROACH. CHANCES ARE IT MAY ALSO HAVE A STRONG IMPACT ON THE WNT-PATHWAY WHICH TRAVEL CLOSE BY AND IS IMPORTANT IN BREAST CANCER!
MTA-1: THIS IS A REAL OPPORTUNITY
Here the cell stopped fooling around trying to lie to you. Here the cell says to you this is one of my way to metastatasize. yes this is my gene to mestastasize and I will work like any CBF like molecule by attaching to DNA and make me protein that will have me spread like wild fire! And by the way I will use a growth hormone like Estrogen. no kidding around
"MTA1 has been shown to interact with HDAC1,[4][5] Histone deacetylase 2,[4][6][5] MTA2,[4] Estrogen receptor alpha[7][5] and MNAT1.[8] MTA1 has also been shown to inhibit SMAD7 at the transcriptional level[9]"
IT DOES NEED TGF TO WORK, TGF IS FOR LOCAL GROWTH ANYWAY THAT WHY IT BLOCKS THE SMAD.
SPINT2
Mutation at SPINT2 leads to significant Malignant Ascites and peritoneal invasion, SPINT 2 is a suppressor of this phenomena. On the Intestinal membrane deficiency of SPINT2 leads to sodium induced/containing diarrhea. This is also true in Ovarian cancer or peritoneal based tumors. Targeting this is better then trying Avastin, a blind approach when it comes to effusions management.
MMP11
A metalloproteiase, aimed at breaking down extracellular matrix and be on the move. Targeting MMP for cancer has proven futile. The cell is not stupid, it does not put out things that is going to hunt it! It build first a strong inhibitor to metalloproteiases. In fact lack of inhibitors has been recognized as the main pathogenesis of TTP. With the ADAMs being the integrins involved! and next is that Inhibitor which is of course expressed in pancreatic cancer.
TIMP1
TIMP1
From Wikipedia, the free encyclopedia
| TIMP metallopeptidase inhibitor 1 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
PDB rendering based on 1d2b. |
|||||||||||
|
|||||||||||
| Identifiers | |||||||||||
| Symbols | TIMP1; CLGI; EPA; EPO; HCI; TIMP | ||||||||||
| External IDs | OMIM: 305370 MGI: 98752 HomoloGene: 36321 GeneCards: TIMP1 Gene | ||||||||||
|
|||||||||||
| RNA expression pattern | |||||||||||
|
|||||||||||
| More reference expression data | |||||||||||
| Orthologs | |||||||||||
| Species | Human | Mouse | |||||||||
| Entrez | 7076 | 21857 | |||||||||
| Ensembl | ENSG00000102265 | ENSMUSG00000001131 | |||||||||
| UniProt | P01033 | P12032 | |||||||||
| RefSeq (mRNA) | NM_003254 | NM_001044384 | |||||||||
| RefSeq (protein) | NP_003245 | NP_001037849 | |||||||||
| Location (UCSC) | Chr X: 47.44 – 47.45 Mb |
Chr X: 20.87 – 20.87 Mb |
|||||||||
| PubMed search | [1] | [2] | |||||||||
This protein a member of the TIMP family. The glycoprotein is a natural inhibitor of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function.
==============
PRKCA see PRKCG
Here Phorbol esters, diacylglycerol, and calcium become important for the cell performance of various functions. Did I mention few targets, I truly believe I did!
CDH1 The Cadherin by excellence, not only important as adhesion molecule and role in metastasis. Its role is amplified by what else anchors here such as Vinculin, and others molecules such as Plakoglobins, amplifying the role. Remember even Cytochrome C is anchored at the mitochondrial membrane and its release leads to apoptosis!
The anchors are legitimate targets therefore, and brings to mind NACA1 in the anchoring to Histone deacetyl transferase (SEE OUR LEUKEMIA SECTION) CDH13 THAT'S ANOTHER BALL GAME ALL TOGETHER. THE CELL TWEACKS SOMETHING AND IT IS ANOTHER BALL GAME ALL TOGETHER!
==========================
ALOX5AP
ACVR1B
PCD1
IRS2
TJP1
MADH6
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