Friday, September 26, 2014

Origin of solid/epithelial and some hematologic tumors: disturbance of Ubiquitilation...

Although there seem to come from every single where,
life seems to try to hide from us the single origin of sufficient disturbance that lead to neoplastic transformation, but every where you turn seems to impose upon us that the single most important process involved in the neoplastic process start as a deficiency in the Ubiquilation process!
Yes one of the E3 (or partner) is involved in many cancer.
The involvement may not be directly involving the cellular E(s), however in many instances, molecules containing a E receptor or attachment site will be involved.
In Breast cancer, the SWI/SNF HAS AN UBIQUITININ BINDING DOMAIN:

"SWI/SNF mutations were widespread across diverse human cancers, with an excess of deleterious mutations, and an overall frequency approaching TP53 mutation. Mutations occurred most commonly in the SMARCA4 enzymatic subunit, and in subunits thought to confer functional specificity (ARID1A, ARID1B, PBRM1, and ARID2). SWI/SNF mutations were not mutually-exclusive of other mutated cancer genes, including TP53 and EZH2 (both previously linked to SWI/SNF). Our findings implicate SWI/SNF as an important but under-recognized tumor suppressor in diverse human cancers, and provide a key resource to guide future investigations."  HUNTER SHAIN et al.
"Remarkably, mutations in SWI/SNF were present at high frequency across many different tumor types (Fig. 1A). The cancers with the highest SWI/SNF mutation rates were ovarian clear cell carcinoma (75%), clear cell renal cell carcinoma (57%), hepatocellular carcinoma (40%), gastric cancer (36%), melanoma (34%), and pancreatic cancer (26%). Across all tumor types, the average frequency of SWI/SNF mutations (19%) approached that of TP53 (26%; shown for comparison in Fig. 1A), the single-most mutated tumor suppressor gene." SHAIN AND JOHNATAN POLLACK

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Mammalian SWI/SNF-A Subunit BAF250/ARID1 Is an E3 Ubiquitin Ligase That Targets Histone H2B[down-pointing small open triangle]

Xuan Shirley L et al"   " together with cullin 2 and Roc1, assemble into an E3 ubiquitin ligase. The BAF250b BC box mutant protein was unstable in vivo and was autoubiquitinated in a manner similar to that for the VHL BC box mutants. The discovery that BAF250 is part of an E3 ubiquitin ligase adds an enzymatic function to the chromatin-remodeling complex SWI/SNF-A."

The part were the SWI/SNF has Histone modulation activity is a relevant one since it points to new creation of sets of molecules that are going to help in the neoplastic transformation.   That in this part of the Silenced DNA, activity at the Ligase will "Unsilence" several genes that will be determinant to the future of the new cell.
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In lung cancers, effects at the MDM-2 has now been recognized by studies by DR Zhang (UTEP) that this is one of the most amplified genetic mutation.  Putting the MDM-2 at the onset of cancer pathogenic production.    Yes the disease seems to start here with further secondary amplification of the NPM1 as a result: 

Robert Amson et al
"TPT1"
and

"recruitment of phosphorylated NPM1 to site of DNA damage through RNF-8-dependent Ubiquitin conjugates" Ayaka Koike et al!
implicating BRCA-1 ....

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The high response rate of Velcade in Myeloma has provided further proof that ubiquitination is a major pathways in this disease
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In renal cancer
the answer is obvious,
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