Thursday, May 2, 2013

RESPONSE TO HYPOXIA
ANGPTL4, ADM
SLC16A3
HER-2 IN BREAST CANCER

FOR AVASTIN RESPONSE.
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You need an intact system in place to obtain Avastin action.
1.   Intact ANGPTL4

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Angiopoietin-like 4
Identifiers
Symbols ANGPTL4; ANGPTL2; ARP4; FIAF; HFARP; NL2; PGAR; pp1158
External IDs OMIM605910 MGI1888999 HomoloGene10755 GeneCards: ANGPTL4 Gene
RNA expression pattern
PBB GE ANGPTL4 221009 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 51129 57875
Ensembl ENSG00000167772 ENSMUSG00000002289
UniProt Q9BY76 Q9Z1P8
RefSeq (mRNA) NM_001039667 NM_020581
RefSeq (protein) NP_001034756 NP_065606
Location (UCSC) Chr 19:
8.43 – 8.44 Mb
Chr 17:
33.77 – 33.78 Mb

PubMed search [1] [2]
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

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)
 

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