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    Defining the Roles of p300/CBP (CREB Binding Protein) and S5a in p53 Polyubiquitination, Degradation and DNA Damage Responses: A Dissertation

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    Authors
    Shi, Dingding
    Faculty Advisor
    Dr. Steven R. Grossman
    Academic Program
    Cancer Biology
    UMass Chan Affiliations
    Medicine
    Program in Cancer Biology
    Document Type
    Doctoral Dissertation
    Publication Date
    2010-01-08
    Keywords
    Genes
    p53
    Tumor Suppressor Protein p53
    p300-CBP Transcription Factors
    CREB-Binding Protein
    E1A-Associated p300 Protein
    Proteasome Endopeptidase Complex
    DNA Damage
    Ubiquitination
    Amino Acids, Peptides, and Proteins
    Cancer Biology
    Genetic Phenomena
    Neoplasms
    Pharmaceutical Preparations
    Therapeutics
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    Abstract
    p53, known as the “guardian of the genome”, is the most well-characterized tumor suppressor gene. The central role of p53 is to prevent genome instability. p53 is the central node in an incredibly elaborate genome defense network for receiving various input stress signals and controlling diverse cellular responses. The final output of this network is determined not only by the p53 protein itself, but also by other p53 cooperating proteins. p300 and CBP (CREB-Binding Protein) act as multifunctional regulators of p53 via acetylase and ubiquitin ligase activities. Prior work in vitro has shown that the N-terminal 595 aa of p300 encode both generic ubiquitin ligase (E3) and p53-directed E4 functions. Analysis of p300 or CBP-deficient cells revealed that both coactivators were required for endogenous p53 polyubiquitination and the normally rapid turnover of p53 in unstressed cells. Unexpectedly, p300/CBP ubiquitin ligase activities were absent in nuclear extracts and exclusively cytoplasmic. In the nucleus, CBP and p300 exhibited differential regulation of p53 gene target expression, C-terminal acetylation, and biologic response after DNA damage. p300 activated, and CBP repressed, PUMA expression, correlating with activating acetylation of p53 C-terminal lysines by p300, and a repressive acetylation of p53 lysine-320 induced by CBP. Consistent with their gene expression effects, CBP deficiency augmented, and p300 deficiency blocked, apoptosis after doxorubicin treatment. Subcellular compartmentalization of p300/CBP’s ubiquitination and transcription activities reconciles seemingly opposed functions—cytoplasmic p300/CBP E4 activities ubiquitinate and destabilize p53, while nuclear p300/CBP direct p53 acetylation, target gene activation, and biological outcome after genotoxic stress. p53 is a prominent tumor suppressor gene and it is mutated in more than 50% of human tumors. Reactivation of endogenous p53 is one therapeutic avenue to stop cancer cell growth. In this thesis, we have identified S5as a critical regulator of p53 degradation and activity. S5a is a non-ATPase subunit in the 19S regulatory particle of the 26S proteasome. Our preliminary data indicates that S5a is required for p53 instability and is a negative regulator of p53 tranactivation. As a negative regulator of p53, S5a may therefore also represent a new target for cancer drug development against tumors that specifically maintain wild type p53.
    DOI
    10.13028/hfsb-j486
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31782
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/hfsb-j486
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