Showing posts with label prostate stem cell antigen. Show all posts
Showing posts with label prostate stem cell antigen. Show all posts

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"

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)

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Jumping translocation breakpoint
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols JTB; HJTB; HSPC222; PAR; hJT
External IDs OMIM604671 MGI1346082 HomoloGene4870 GeneCards: JTB Gene
RNA expression pattern
PBB GE JTB 210434 x at tn.png
PBB GE JTB 210927 x at tn.png
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
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-beta1-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."
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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."
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