Lung cancer, one of the leading deadly cancers for which screening has not clearly be established, has been one of the target of many researches. To this day, only radiological evaluations have creeped up to a level of screening. With the advance of technology, we have gone from Chest Xray to low-dose cat scans for this indication. And this despite our progress in the knowledge of genetics.
Quite frankly it seems that much of preliminary genetic knowledge has been developed. The amount of information available on genes of cancer is impressive. What is missing is boldness of our scientists to form theories of progression of this disease which kill many victims each year. The neoplastic process however continues to occur steadily, and year after year, new lung cancers are being brought to light through detection that is characteristically late. There are many lung cancers and none appears to have the same pathophysiologic occurrence mechanism. So in this maze of mechanisms, finding a steady gene abnormality that does vary very much through stages of cancer appears a significant fact! Indeed the MDM-2 Mutation appears steadily throughout the stages of certain lung cancers, particularly the Adenocarcinomas. Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase is the gene in question! In our sample, this gene was the highest present and its presence seemed to vary little both on cancer tissues and in the serum of diseased patients. These specimen were provided to CRBCM and the UTEP biologic research laboratory by LCBRN -VA university tissue bank (under MDHONORS funding).
Coming back to the MDM-2:
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When one lean on this finding in depth, the puzzle for the involvement of the MDM-2 runs deeper than first suspected. And clearly lays in the dawn of the neoplastic process. And as we lean further, new suspicions rise that the onset of the neoplasia for some cancers is here! Several facts contribute to this perception. We all know that cigarette smoking is a common cause of lung cancer, and now this known fact...
Dr Yurong Chai, our investigator stressed that Cigarette smoke "increase the risk of alternative MDM-2 splicing" a fact that establishes the initial event that will trigger so much subsequent genetic calamities. MDM-2 happens to be the regulator of P53. It also has a competitive partner, the FKBP25,
OCHOKA"
"The p53 tumour suppressor protein is tightly controlled by the E3
ubiquitin ligase, mouse double minute 2 (MDM2), but maintains MDM2
expression as part of a negative feedback loop. We have identified the
immunophilin, 25kDa FK506-binding protein (FKBP25), previously shown to
be regulated by p53-mediated repression, as an MDM2-interacting partner.
We show that FKBP25 stimulates auto-ubiquitylation and proteasomal
degradation of MDM2, leading to the induction of p53. Depletion of
FKBP25 by siRNA leads to increased levels of MDM2 and a corresponding
reduction in p53 and p21 levels. These data are consistent with the idea
that FKBP25 contributes to regulation of the p53-MDM2 negative feedback
loop." The impact on a member of the FK506 family has deep implications both on the disease process and therapeutically as we may discuss.
The involvement of disturbances of the MDM-2 has even deeper consequences, because of independent MDM-2 activity directly on initiation of DNA replication and through its activity on Cyclin-depedent Kinases! The MDM-2 rise quickly as a biomarker of Cancer initiation and therefore a major Biomarker of the danger of smoking! And its presence no matter the stage of disease has several implications including that of how you appreciate curability! (to be continued)
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