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Role And Regulation Of Hausp In Cancer

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Title Role And Regulation Of Hausp In Cancer
 
Creator Bhattacharya, Seemana
 
Subject Cell Biology & Physiology
 
Description Cancer is a disease of uncontrolled cell growth resulting from deregulated cellular signaling. Signal transduction is subject to several modes of regulation.This study is focussed on post-translational modifications, especially
deubiquitination. The thesis work is divided into four sections, the first three emphasize on the role of HAUSP and the fourth one is on the regulation of
HAUSP.In the first part of the work, we have found a large number of putative substrates of HAUSP by MALDI-TOF/TOF MS/MS analysis. We have shown the effects of exogenously expressed HAUSP on the overall proteome. To further
investigate the interacting partners of HAUSP, the pool of interacting proteins was enriched by immunoprecipitation. Gene ontology based analysis of the proteins
identified, indicate a probable involvement of HAUSP in tumor suppression, metabolism, cytoskeletal organization and transport, gene expression, chaperone system, apoptosis, etc. A few uncharacterized/ novel proteins have also been identified. From the analysis, three putative bona fide substrates – TRRAP, Keratin and FBF-1 have been identified which were also found to colocalize with
HAUSP. In this part of the work we have shown that HAUSP plays an important role in cancer by regulating cMyc via TRRAP.In the second part, we have identified Rb as a novel substrate for HAUSP mediated deubiquitination. This has added an edge to the MDM2 – p53 mediated functions of HAUSP. We have shown the role of HAUSP in preferential
stabilization of MDM2 over Rb in cancer/ GBM cell lines. In delineating the mechanism of the phenomena, we show how HAUSP stabilizes Rb in a contextPreface dependent manner, using a p53-independent switching mechanism in normal and
cancer cells, where MDM2 is the critical regulator.
In the third part, we have identified the role of HAUSP specifically in glioma. In clinical specimens of glioma we have shown that HAUSP protein levels increase during progression from lower to higher grad(immunohistochemistry). This is very well corroborated by the in vitro data showing knockdown of HAUSP leads to huge decrease in the cellular proliferation as seen in U87MG cells while upregulation of HAUSP led to larger
sized and more number of colonies in a colony formation assay.In the fourth and last part of the work on regulation of HAUSP, first we found that in U87MG (GBM) cells HAUSP is regulated by EGF stimulation, wherein HAUSP transcript levels show a huge increase upon EGF treatment and
at the protein level we see a clear nuclear exclusion within a short period of induction. The most appropriate explanation here at this point of time would be
that in U87MG cells which harbor wild type p53, HAUSP nuclear exclusion would lead to destabilization of p53 in the nucleus, thus preventing its function as
a tumor suppressive transcription factor. Upon in silico analysis of the HAUSP promoter sequence we identified a large number of p53 binding sites giving rise to
the possible existence of a feedback regulation of HAUSP by p53. Additionally the presence of TCF4/LEF sites is also suggestive of a role of Wnt signaling in regulating HAUSP.
 
Date 2014
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2059/1/Seemana_Bhattacharya%2DFull_Thesis.pdf
Bhattacharya, Seemana (2014) Role And Regulation Of Hausp In Cancer. PhD thesis, Calcutta University.
 
Relation http://www.eprints.iicb.res.in/2059/