Identification of Alternative Hif-1a Dimerization artners in Arnt (Hifljff)-null

Columbia University Health Sciences, New York NY

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Abstract

Members of the p53 tumor suppressor family (p53, p63 and p73) play critical roles in cell function, animal[unreadable] development and tumor suppression. P63 in particular is known to be crucial for the development of the[unreadable] epidermis. p63 mRNAs can be transcribed through two promoters to produce different N-termini that[unreadable] determine whether they contain (TA) or lack (DN) a full activation domain. TAp63 has been recently[unreadable] proposed to direct keratinocyte commitment during embryogenesis, while DNp63 is the dominant isoform[unreadable] found in both normal and neoplastic keratinocytes with high proliferative potential. Since the molecular[unreadable] mechanisms underlying p63 functions are still largely unknown, we propose to study this by the following[unreadable] approaches.[unreadable] First, we have performed exhaustive yeast two hybrid screening using a human keratinocyte cDNA library[unreadable] and have identified 4 novel p63 interactive partners. We are currently investigating biological functions that[unreadable] are mediated by p63 and its binding partners. Second, the cross talk between p63 and its family members[unreadable] (p53 and TAp63) will be investigated. It has been found that DNp63, the major p63 isoform in keratinocytes,[unreadable] can suppress the activity of p53 and TAp63 in reporter assays. We plan to examine whether DNp63 can[unreadable] inhibit the activity of p53 and TAp63 in vivo, and whether such activity is regulated by the p63-bidning[unreadable] proteins. Third, we will search for direct target genes bound by p63 in keratinocytes using both chromosome[unreadable] immunoprecipitation protocol and DNA microarray analysis. Once those genes are identified, how p63[unreadable] (together with its binding proteins) regulates them and what their roles in keratinocytes will be further[unreadable] pursued.