Accession Number : ADA599799


Title :   P53 Suppression of Homologous Recombination and Tumorigenesis


Descriptive Note : Annual summary rept. 1 Jan 2010-30 Jun 2013


Corporate Author : TEXAS UNIV HEALTH SCIENCE CENTER AT SAN ANTONIO


Personal Author(s) : Karia, Bijal


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a599799.pdf


Report Date : Jul 2013


Pagination or Media Count : 211


Abstract : p53 is the most studied protein in cancer; however, the complex multifunctional nature of p53 has made understanding it s mechanism(s) of tumor suppression difficult. The p53 protein is not essential for life as p53 nullizygous mice are viable. Nonetheless, p53 is important for responding to cellular stresses that disrupt the normal cellular homeostasis and threaten genomic integrity. To date many in vitro, tissue culture and mouse models have been created to study functions of p53. Mouse models that retain certain aspects of p53 function (cell cycle arrest and/or apoptosis) still succumb to spontaneous tumors, suggesting that multiple facets of p53 function that remain poorly defined are involved. Here, we evaluate whether two separation-of-function p53 mutants can affect homologous recombination and ask how this impacts genomic stability. The role of p53 in homologous recombination has been somewhat controversial and its relevance to general genome stability and tumor suppression poorly evaluated. We use a mouse model, pink-eyed unstable, to assess homologous recombination in vivo during somatic development for two p53 point mutation models. The p53 R172P homozygous mutant retains the ability to arrest the cell cycle, but is incapable of eliciting apoptosis. This mutant suppressed homologous recombination similar to wildtype p53. The more aggressive p53 R172H dominant negative mutant has a dysregulated DNA binding domain and is incapable of either transactivating known p53 target genes or binding proteins whose interaction is mediated by this domain. This mutant has lost the capability to suppress homologous recombination similar to the p53 nullizygous mouse. The pink-eyed unstable assay is based on the deletion of one copy of a 70 kb tandem duplication, essentially a copy number variant. We examined the status of copy number variations in the genome by performing array comparative genomic hybridization on cells derived from the two-p53 mutant mice.


Descriptors :   *BREAST CANCER , *IN VITRO ANALYSIS , APOPTOSIS , CELLS(BIOLOGY) , DEOXYRIBONUCLEIC ACIDS , GENOME , GROWTH(PHYSIOLOGY) , NEOPLASMS , PROTEINS , TISSUE CULTURE


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE