. In the past few years, the applicant states that she has developed an interest in the molecular mechanisms regulating the aging process, both in vitro and in vivo. She has focused studies primarily on the skin, but has recently extended some of the cutaneous observations to other organ systems. As a fellow, she has studied one class of transcription factors, the nuclear receptors for retinoic acid, and has demonstrated, with colleagues, the selective up-regulation of RAR beta2 in senescent cells from two distinct human cell types, human dermal fibroblasts and human mammary epithelial cells. She and her group have examined this event independent of the age of the donor, and have provided data that the mechanism regulating this event is transcriptional. They have also explored the functional consequences of this event and have shown that RAR beta2 can, under certain circumstances, function as a suppressor of transformation and inhibitor of cell proliferation. In this proposal, the intent is to extend these studies with structure-function analyses of retinoid-regulated signal transduction pathways in senescent cells. In four specific aims, they plan to test hypotheses that will allow them to determine the cis-acting sequences and the trans-acting factors mediating the transcriptional up-regulation of RAR beta2 in senescent cells. Further, they will use in vitro mutagenesis to determine the mechanism by which this gene inhibits cell proliferation, and hence may function as a tumor suppressor. In this way, they hope to gain insight into the molecular mechanisms regulating the senescent phenotype in these two cell types, and gain further understanding of the anti-proliferative properties of this multigene family. They also hope to identify genes which may play a role in tumor suppression, and whose loss of function is important in both human breast cancer and skin cancer.
