Coalition for the Reversal of Breast Cancer Mortality in African American Women

More reference expression data

ANGPTL4; ANGPTL2; ARP4; FIAF; HFARP; NL2; PGAR; pp1158

External IDs

OMIM: 605910 MGI: 1888999 HomoloGene: 10755 GeneCards: ANGPTL4 Gene

[show]Gene Ontology

RNA expression pattern

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 19:
8.43 – 8.44 Mb

Chr 17:
33.77 – 33.78 Mb

PubMed search

Angiopoietin-related protein 4 is a protein that in humans is encoded by the ANGPTL4 gene.^[1]^[2]^[3] Alternatively spliced transcript variants encoding different isoforms have been described. This gene was previously referred to as ANGPTL2, HFARP, PGAR, or FIAF but has been renamed ANGPTL4.

This gene is induced under hypoxic (low oxygen) conditions in various cell types and is the target of Peroxisome proliferator-activated receptors. The encoded protein is a serum hormone directly involved in regulating lipid metabolism and also acts as an apoptosis survival factor for vascular endothelial cells.

Clinical significance

The encoded protein may play a role in several cancers and it also has been shown to prevent the metastatic process by inhibiting vascular activity as well as tumor cell motility and invasiveness. ANGPTL4 contributed to tumor growth and protected cells from anoikis, a form of programmed cell death induced when contact-dependent cells detach from the surrounding tissue matrix. ANGPTL4 secreted from tumors can bind to integrins, activating downstream signaling and leading to the production of superoxide to promote tumorigenesis.^[5] ANGPTL4 disrupts endothelial cell junctions by directly interacting with integrin, VE-cadherin and claudin-5 in a sequential manner to facilitates metastasis. ANGPTL4 functions as a matricellular protein^[6] to facilitates skin wound healing. ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration. ANGPTL4 inhibits lipoprotein lipase, LPL, by breaking the dimer molecule. ANGPTL4 has been unambiguously established as a potent inhibitor of blood plasma Triglyceride (TG) clearance, causing elevation of plasma TG levels. As a consequence, ANGPTL4 knockout mice have reduced serum triglyceride levels, whereas the opposite is true for mice over-expressing ANGPTL4. The reduction in LPL activity in adipose tissue during fasting is likely caused by increased local production of ANGPTL4. In other tissues such as heart, production of ANGPTL4 is stimulated by fatty acids and may serve to protect cells against excess fat uptake.^[7]"

IF YOU LIKE YOUR PATIENT WITH CANCER, INHIBIT THIS MOLECULE WITH MIGHTY FORCE AND DO THIS PERSISTENTLY. WONDER WHY AVASTIN SHOULD NOT BE STOPPED UNTIL CLEAR EVIDENCE OF FAILURE IS DISPLAYED? READ THIS AGAIN!   THIS IS A POWERFUL TARGET AND GIVES YOU THE SECRET TO AVASTIN POWERS IN METASTATIC DISEASES!

Decreased expression of this protein has been associated with type 2 diabetes. AND COULD CONTRIBUTE TO WHY LESS CANCERS ARE OBSERVED IN DIABETIC, AND WHY TRIGLYCERIDES GO WILD IN DIABETICS.

GRAY ET AL ADDED:
"Glucocorticoid receptor blockade prevented fasting-induced tissue Angptl4 expression and WAT TG hydrolysis in mice, and TG hydrolysis induced by fasts of 6 or 24 h was greatly reduced in mice lacking Angptl4 (Angptl4(-/-)). Glucocorticoid treatment mimicked the lipolytic effects of fasting, although with slower kinetics, and this too required Angptl4. Thus, fasting-induced WAT TG hydrolysis requires glucocorticoid action and Angptl4."   LOW DOSE PREDNISONE USED IN PROSTATE CANCER PROTOCOLS MAY BE VALUABLE BECAUSE OF THIS!
IT IS ALSO THE KEY TO WHY AVASTIN IS GOOD IN KEEPING PEOPLE FROM MALIGNANT ASCITES.   KNOCK OFF MICE DIE WITH ASCITES !
?IS THIS THE SINGLE MOLECULE EXPLAINING FLUID RETENTION OF STEROIDS, IT MUST CONTRIBUTE I BELIEVE! CERTAINLY, LIPODYSTROPHY IS EXPLAINED TOO!

2.ADM GENE

IF YOU SEARCH WHY AVASTIN TREATMENT IS COMPLICATED BY HYPERTENSION, WELL IT BLOCK VASODILATORS SUCH AS THE ADM GENE.

WIKIPEDIA

"

Receptors of Adrenomedullin

Main article: Adrenomedullin receptor

At present AM is believed to function through combinations of the calcitonin receptor like receptor (CALCRL) and receptor activity-modifying proteins (RAMP2) complexes, as well as CGRP receptors. It is worth noting that unlike the classical one ligand-one receptor notion of receptor signalling, the interaction of both Calcitonin receptor-like (CALCRL) and RAMP ( Receptor activity-modifying protein) at the membrane, is required for AM to mediate its action. The outcome of AM stimulation of its receptor is the cellular production of both cyclic AMP (cAMP) and nitric oxide production. Some may find the production of these inside the cell to be at odds, since often they have opposing effects, but as yet, the timing of these effects remains to be studied.^{[citation needed]}

The physiological functions of Adrenomedullin

AM was initially identified as a vasodilator, some have cited this as the most potent endogenous vasodilatory peptide found in the body (Cockcroft et al., 1997). Differences in opinion regarding the ability of AM to relax vascular tone arises from the differences in the model system used (Hamid and Baxter, 2005). Other effects of AM include increasing the tolerance of cells to oxidative stress and hypoxic injury and angiogenesis. AM is seen as a positive influence in diseases such as hypertension, myocardial infarction, chronic obstructive pulmonary disease and other cardiovascular diseases, whereas it can be seen as a negative factor in potentiating the potential of cancerous cells to extend their blood supply and cause cell proliferation."

THIS KNOWLEDGE CAN HELP PICK THE BEST TREATMENT FOR COMPLICATION BY HYPERTENSION DURING AVASTIN USE! INCIDENTALLY, IT UNVAIL THE RAMP2 AS A SECONDARY TARGET. REMEMBER PERTURBING TRANSFER OF RECEPTOR IS A VALID THERAPEUTIC INTERVENTION CALLED "MISLOCALIZATION ".

" The protein encoded by this gene is a member of the RAMP family of single-transmembrane-domain proteins, called receptor (calcitonin) activity modifying proteins (RAMPs). RAMPs are type I transmembrane proteins with an extracellular N-terminus and a cytoplasmic C-terminus. RAMPs are required to transport calcitonin-receptor-like receptor (CRLR) to the plasma membrane. CRLR, a receptor with seven transmembrane domains, can function as either a calcitonin gene-related peptide (CGRP) receptor or an adrenomedullin receptor, depending on which members of the RAMP family are expressed. In the presence of this (RAMP2) protein, CRLR functions as an adrenomedullin receptor. The RAMP2 protein is involved in core glycosylation and transportation of adrenomedullin receptor to the cell surface.^{[1] WIKIPEDIA"}

^{3.ANOTHER MISLOCALIZATION TARGET? THIS ONE IN THE MEMBRANE!}
Entrez Gene summary for SLC16A3:

Lactic acid and pyruvate transport across plasma membranes is catalyzed by members of the proton-linked monocarboxylate

transporter (MCT) family, which has been designated solute carrier family-16. Each MCT appears to have slightly

different substrate and inhibitor specificities and transport kinetics, which are related to the metabolic

requirements of the tissues in which it is found. The MCTs, which include MCT1 (SLC16A1; MIM 600682) and MCT2

(SLC16A7; MIM 603654), are characterized by 12 predicted transmembrane domains (Price et al., 1998 (PubMed

9425115)).(supplied by OMIM, Mar 2008)

Wednesday, May 1, 2013

A novel virus genome discovered in an extreme environment suggests recombination between unrelated groups of RNA and DNA viruses

Geoffrey S Diemer and Kenneth M Stedman^*

^{GO to the article !}

^{This story truly deserve the reward given to those scientists}
^{it is the story introducing the 9th law of nature}
^{which is the law of adaptation to unusual conditions by adjusting genetic potential, by the power of recombination, and using cellular heterogeneity, and by activating NF-kB.}
^{cells have an incredible versatility potential if given the time and if the programmed death is not triggered by an overwhelming stimulant... to adapt and develop new function ready to deal with change in the environment. These changes could be dramatic! ie we lost our tail for god sake!}
^{The reversal of mesenchymal transformation is another of change to adaptation and is the underlying reason of deviation of epithelialization driving the Barrett transformation in the lower 3rd of the Esophagus. These changes are benign until receptor become desensitized to an overwhelming and relentless stimulation leading to the HSP (heat stroke protein ) gets as well as the provoked! Prevention of progression to cancer should dampen growth factors and decrease HSP actions!}
^{We have recently hypothesized that the MEK action as well as the Wnt were membrane located and followed the Reticulum Endothelium tract to reach the nucleus. With the involvement of the Hedgehog, Basaloid morphology resulted in triple negative breast cancer! (Again if it is strong enough to induce a morphologic change, it is strong enough to cause an abnormality so significant as a neoplastic process.-even Fanconi abnormality associated with morphology changes (microcephaly) will lead to a Myelodysplastic Syndrome. (and we contend that these type of syndrome will respond to Revlimid and Thalidomide type of drugs). We promise to discuss the gene involved in the 9th law soon but this text tells you already where we are going to fish them!}

REMEMBER THE BRCA FAMILY IS NOT THE ONLY DNA REPAIR GENE FAMILY!

1.NBS gene:
============
Nijmegen breakage syndrome

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Nijmegen breakage syndrome
Classification and external resources
OMIM	251260
DiseasesDB	32395
eMedicine	derm/725
MeSH	D049932

Nijmegen breakage syndrome (NBS), also known as Berlin breakage syndrome and Seemanova syndrome, is a rare autosomal recessive^[1] congenital disorder causing chromosomal instability, probably as a result of a defect in the Double Holliday junction DNA repair mechanism.
NBS1 codes for a protein that has two major functions: (1) to stop the cell cycle in the S phase, when there are errors in the cell DNA (2) to interact with FANCD2 that can activate the BRCA1/BRCA2 pathway of DNA repair. This explains clearly that mutations in the NBS1 gene lead to higher levels of cancer (see Fanconi anemia, Cockayne syndrome...)
The name derives from the Dutch city Nijmegen where the condition was first described.^[2]
Most people with NBS have West Slavic origins. The largest number of them live in Poland.
Mrs Seemanova MD after whom the name of the syndrome was given, currently works at Motol Hospital, Prague, Czech Republic, as a Professor of medical genetics.===============================================

2. BLM gene
Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.^[1]
The Bloom syndrome gene product is related to the RecQ subset of DExH box-containing DNA helicases and has both DNA-stimulated ATPase and ATP-dependent DNA helicase activities. Mutations causing Bloom syndrome delete or alter helicase motifs and may disable the 3' → 5' helicase activity. The normal protein may act to suppress inappropriate homologous recombination.^[2]

Interactions

Bloom syndrome protein has been shown to interact with CHEK1,^[3] Replication protein A1,^[4]^[5]^[6] Werner syndrome ATP-dependent helicase,^[7] RAD51L3,^[8] Ataxia telangiectasia mutated,^[9]^[10] RAD51,^[11] XRCC2,^[8] Flap structure-specific endonuclease 1,^[12] H2AFX,^[3] TP53BP1,^[3] FANCM,^[13] P53,^[3]^[14]^[15]^[16] TOP3A,^[4]^[17]^[18]^[19] MLH1^[9]^[18]^[20]^[21] and CHAF1A.^[22]

TO UNDERSTAND THAT THE BLM GENE IS A DNA REPAIR GENE, YOU MUST REMEMBER WHAT A 'HELICASE' IS:

Helicase

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Structure of E. coli helicase RuvA

DNA helicase

Identifiers

Databases

PDB structures

[show]Search

RNA helicase

Identifiers

Databases

PDB structures

[show]Search

Helicases are a class of enzymes vital to all living organisms. Their main function is to unpackage an organism's genes. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands (i.e., DNA, RNA, or RNA-DNA hybrid) using energy derived from ATP hydrolysis. There are many helicases resulting from the great variety of processes in which strand separation must be catalyzed. Approximately 1% of eukaryotic genes code for helicases.^[1] In humans, 95 non-redundant helicases are coded for in the genome, 64 RNA helicases and 31 DNA helicases.^[2] Many cellular processes, such as DNA replication, transcription, translation, recombination, DNA repair, and ribosome biogenesis involve the separation of nucleic acid strands that necessitates the use of helicases.
KEEFE ET AL" Bloom syndrome occurs most frequently in the Ashkenazi Jewish population with patients almost exclusively homozygous for a frameshift mutation resulting from a 6 bp deletion/7 bp insertion at nucleotide 2,281 (BLMAsh). This mutation causes premature termination of the encoded gene product producing a truncated protein of 739 amino acids while the full length protein contains 1417 amino acids.
The mutated gene in Bloom syndrome, BLM, was localized to chromosome 15q26.1 and encodes a member of the RecQ family of DNA helicases. This family also contains several other genes that are associated with disease phenotypes including the Werner Syndrome protein (WRN) and the defective protein in Rothmund-Thomson syndrome (RecQL4). Both of these diseases also feature an increased incidence of cancer. BLM, along with the rest of the members of this family, exhibits 3'-5' helicase activity and plays a role in DNA repair and recombination. BLM functions during replication stress and is required for the recruitment of several other important repair proteins including NBS1, BRCA1, Rad51 and MLH1. In addition, the BLM helicase is involved in recombinational repair events as evidenced by its ability to promote branch migrations of Holliday junctions at stalled replication forks. BLM may also play a role in apoptosis since it directly interacts with p53 and helps regulate its transcriptional activity."
=========================================================================

3.ATM gene
Ataxia telangiectasia mutated

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Ataxia telangiectasia mutated

Identifiers

Chr 11:
108.09 – 108.24 Mb

ATM; AT1; ATA; ATC; ATD; ATDC; ATE; TEL1; TELO1

External IDs

OMIM: 607585 MGI: 107202 HomoloGene: 30952 ChEMBL: 3797 GeneCards: ATM Gene

EC number

2.7.11.1

[show]Gene Ontology

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 9:
53.44 – 53.54 Mb

PubMed search

Ataxia telangiectasia mutated (ATM) is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2 and H2AX are tumor suppressors.
The protein is named for the disorder Ataxia telangiectasia caused by mutations of ATM.^[1]

GOLDGAR ET AL suggested:

"The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2."

=============================================================

4. MRE 11 gene

MRE11A

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MRE11 meiotic recombination 11 homolog A (S. cerevisiae)

Available structures

PDB

Ortholog search: PDBe, RCSB

[show]List of PDB id codes

Identifiers

More reference expression data

MRE11A; ATLD; HNGS1; MRE11; MRE11B

External IDs

OMIM: 600814 MGI: 1100512 HomoloGene: 4083 GeneCards: MRE11A Gene

[show]Gene Ontology

RNA expression pattern

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 11:
94.15 – 94.23 Mb

Chr 9:
14.78 – 14.84 Mb

PubMed search

Double-strand break repair protein MRE11A is a protein that in humans is encoded by the MRE11A gene.^[1]
This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms.^[2]

Interactions

MRE11A has been shown to interact with Ku70,^[3] Ataxia telangiectasia mutated,^[4]^[5] MDC1,^[6] Rad50,^[3]^[5]^[7]^[8]^[9] Nibrin,^[5]^[9]^[10]^[11]^[12] TERF2^[13] and BRCA1.^[5]^[7]^[14]^[15]

FUKUDA ET AL

"MRE11, RAD50, and XRS2 have been identified in yeast as components of the HR and NHEJ pathways (4) . A physical complex with these proteins has been identified. In vertebrates, MRE11 and RAD50 form a complex with NBS1, whose mutation causes NBS (5 , 6) . The clinical features of NBS overlap with those of AT. They are characterized by chromosome instability, increased hypersensitivity to ionizing radiation, immunodeficiency, and predisposition to cancer. AT is caused by mutations in the ATM gene, which encodes a protein kinase homologous with phosphatidylinositol-3 kinase (7) . ATM is a key regulator of the cellular response to DSBs. NBS1 is phosphorylated in an ATM-dependent manner after ionizing radiation, suggesting a link between ATM and NBS1 in a common signaling pathway (8) . MRE11 phosphorylation upon DNA damage is dependent on NBS1 (9) . Therefore, it is highly likely that MRE11 participates in the same pathway in response to DNA damage. Consistent with this functional interaction, hypomorphic mutations in the MRE11 gene cause ataxia-telangiectasia-like disorder, the phenotypes of which are indistinguishable from those of AT (10) ."

ATM mutations play a causal role in AT and have been demonstrated in lymphoid malignancies
======================================================================

5. RAD51

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RAD51 homolog (S. cerevisiae)

A filament of Rad51 based on PDB 1SZP.^[1]

Available structures

PDB

Ortholog search: PDBe, RCSB

[show]List of PDB id codes

Identifiers

More reference expression data

RAD51; BRCC5; HRAD51; HsRad51; HsT16930; MRMV2; RAD51A; RECA

External IDs

OMIM: 179617 MGI: 97890 HomoloGene: 2155 GeneCards: RAD51 Gene

[show]Gene Ontology

RNA expression pattern

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 15:
40.99 – 41.02 Mb

Chr 2:
119.11 – 119.15 Mb

PubMed search