Cancers occur from mutations of DNA which alters regulatory checks and balances that control cellular growth and differentiation and gives these cells a growth advantage. Loss of genetic material may be oncogenic by resulting in the loss of a growth regulator that normally constrains cellular proliferation. The loss removes the normal inhibitions of cellular growth. These genes have been called one of several names including tumor suppressor genes, recessive oncogenes or anti-oncogenes. Data suggest that p53 gene can function as a tumor suppressor. p53 will be used as a paradigm to study the role of tumor suppressor genes in ovarian cancers as well as cancers in general: 1.) Determine frequency and type of p53 mutations in ovarian cancers and correlate alterations in p53 expression with clinical and histological parameters of the patient. 2.) Use p53 sense and antisense expression vectors and antisense oligonucleotides to determine functional significance of p53 in ovarian cancer cells. 3.) Define the role of p53 as a transcriptional activator. Our initial studies show that the 1st 160 amino acids of the amino terminus of p53 is able to transactivate other genes. We will further sublocalize the transactivating sequences of p53. In addition, we will study the effect of p53 mutations in each of four conserved regions of the p53 protein, as well as the effect of E1B (55,000 dalton protein) and T-Ag of SV-40 on transactivation by p53. 4.) Use homologous recombination of a mutated p53 as an approach to study cancer. We will develop and study mice who are either heterozygous or homozygous for a mutated, non-functional p53 in order to understand if the gene has a function in defense against cancer. Taken together, these studies of p53 will provide a model to understand the role of tumor suppressor genes in ovarian cancer and in cancers in general.
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