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Functional Significance of Mutant p53 in Breast Cancer

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Annual summary rept. 1 Jul 1999-30 Jun 2002

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Approximately 50 of human cancers have accumulated missense mutations in the gatekeeping tumor suppressor protein p53, usually resulting in genomic instability and a very poor prognosis. The wild-type p53 protein is required for assessing DNA damage in cells and making the decision to either induce cell cycle arrest to facilitate DNA repair, or to induce a suicide response in those cells with irreparable damage. In human tumors, many hot-spot mutations are found within the DNA-binding domain of p53, rendering it incapable of sequence-specific transactivation of target genes such as p2l, bax, and mdm2. Some of these mutants, in addition to having dominant-negative functions, also gain novel functions by interacting with proteins differently from the wild-type p53 protein. One such gain-of-function p53 mutant possesses an Arg to His substitution at codon l75 l72 in mice and has been shown to be involved in the dysregulation of centrosome duplication leading to abnormal mitoses and subsequent aneuploidy. Because centrosome abnormalities and aneuploidy are often seen in high-grade breast tumors, unraveling the mechanism behind the involvement of p53l72 R-H in centrosome dysregulation will help us to understand the progression of mammary carcinogenesis. In order to identify potential indirect target genes regulated by this mutant, we employed a suppressive subtractive hybridization technique to generate a cDNA library specific to p53 null mammary epithelial cells MECs expressing the l72 R-H mutant. cDNA made from p53 null mammary epithelial cells transiently transfected with wild-type p53 was subtracted from cDNA made from mutant p53 transfected cells. The subtraction procedure generated a pool of cDNAs differentially expressed in the presence of the mutant protein many interesting genes were revealed to be candidates for regulation by mutant p53. Some of these include developmental, metabolic, transcriptional,

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  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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