ROLE OF P270 IN DIFFERENTIATION AND TUMORIGENESIS

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DESCRIPTION (Applicant's Description): Recent isolation of Drosophila and mammalian homologs of many of the yeast SWI/SNF complex members suggest that these complexes play fundamental roles in the regulation of gene expression during cell growth and development in all organisms. Alterations in some of these proteins have been associated with the tumorigenic phenotype. Loss of the human SWI2 homologs Brg1 and hBrm have been demonstrated in the cancer cell lines C33 and SW13. Biallelic alterations of the hSNF5/INI1 gene were discovered in malignant rhabdoid tumors. p270 is an integral member of human SWI/SNF complexes, first identified in my lab through its shared antigenic specificity with p300 and CBP. Sequence analysis of p270 suggests it is the mammalian homolog of SWI1. The function of p270 in the SWI/SNF complex is not known, but certain motifs provide a clue. p270 contains four LXXLL motifs demonstrated to bind nuclear hormone receptors. p270 also contains a recently defined ARID (AT-Rich Interaction Domain) DNA binding consensus sequence. These regions of p270 and its location in the SWI/SNF complex, which appears to mediate tissue specific gene expression and to contain chromatin remodeling activities, suggest a potential function for p270 as an integrator of hormone signaling and transcription initiation. This potential function of p270 suggests it will play an important role in hormonally driven differentiation. I propose to study the structure and function relationship of p270 with a focus on the roles of the LXXLL motifs and activity of the protein on nuclear hormone signaling during differentiation, with an emphasis on glucocorticoid driven adipocyte differentiation. Specifically I propose to: identify the protein interactions mediated by the LXXLL motifs in p270; determine the effect of hormones on activity and expression of p270; and determine whether p270 contributes to cell growth control.