Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.625189
Title: A study on the regulation of iASPP
Author: Hu, Y.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2009
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Abstract:
The identification of the ASPP family of proteins (ASPP1, ASPP2 and iASPP) has helped facilitate a better understanding of how the functions of the tumour suppressor p53 are specifically regulated. ASPP1 and ASPP2 bind to p53 and specifically enhance its transcriptional activities on proapoptotic genes, while iASPP, by a similar mechanism, inhibits p53. However, iASPP is also an inhibitor of NFκB and may, therefore, inhibit cell proliferation. Many other proteins have also been reported to bind with iASPP, suggesting that p53- or NFκB-independent functions may also exist. However, the mechanisms by which iASPP activity is regulated remain unclear. In this thesis, iASPP has been shown to be phosphorylated by at least two families of non-receptor tyrosine kinases: Src and Abl. Tyrosine phosphorylation of iASPP at Y132 is mainly due to the activation of Src family kinases. Upon phosphorylation at Y132, iASPP is translocated to adherens junctions and focal adhesions, where it forms stable multiprotein complexes with either cadherin/catenins or focal adhesion proteins. Importantly, phosphorylation deficient Y132F-iASPP increases cell motility in MCF-7 cells. A potential negative effect of pY132-iASPP on cell motility has, therefore, been suggested. Oncogenic Bcr-Abl kinase is the underlying cause of chronic myeloid leukaemia (CML). pY-iASPP levels are increased with Bcr-Abl expression, while a specific Abl kinase inhibitor called STI-571, which has been successfully used to treat CML, efficiently inhibits this production of pY-iASPP. These data suggest that iASPP may be a downstream effector by which Bcr-Abl transforms blood cells, and a potential marker to predict the response of CML patients to STI-571 treatment. In addition, iASPP’s functions may be regulated by caspase cleavage in death receptor induced apoptosis of leukaemia cells. This cleavage mechanism produces a 80kDa iASPP fragment (295-828), which loses all identified tyrosine phosphorylation sites at the N-termini, suggesting that cells may prevent the production of pY-iASPP by caspase cleavage to affect the progress of apoptosis. Taken together, the results presented in this thesis provide insights into the posttranslational regulation of iASPP activity, which will lead to a better understanding for both cancer biology and cancer therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.625189  DOI: Not available
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