YPEL3, A Growth Suppressive Gene That Induces Cellular Senescence

Abstract

<p>Cellular senescence, the limited ability of cultured normal cells to divide, can result from cellular damage triggered through oncogene activation (premature senescence) or the loss of telomeres following successive rounds of DNA replication (replicative senescence). Both processes require a functional pS3 signaling pathway. The tumor suppressor protein, pS3, acts as a transcription factor that's activated in response to DNA damage and regulates genes involved in various processes including senescence. Relevant downstream pS3 targets associated with senescence induction have been difficult to identify. Discovery of senescence activators is important because induction of tumor cell senescence may represent a therapeutic approach for the treatment of cancer. In microarray studies where the tumor suppressor pS3 was reactivated in MCF7 cells, we discovered that YPEL3 (Yippee-like-3), a member of a recently discovered family of putative zinc finger motif coding genes consisting of YPEL1-S, is a pS3regulated gene. Upon validation of this microarray finding, we investigated the biological role of YPEL3 induction in human cells. The physiological induction of YPEL3 results in a decrease in cell viability associated with an increase in cellular senescence. Through the use of RNAi and H-ras induction of senescence, we demonstrate that YPEL3 activates cellular senescence downstream of pS3. Moreover, using various breast carcinoma cell lines we have uncovered that YPEL3 expression is decreased in response to estrogen in ER+ breast cancer cells and removal of estrogen leads to an increase in YPEL3 expression and senescence induction in these cells. Together these results indicate that YPEL3 may serve as a potential senescence associated target useful to anti-cancer drug design. We believe these findings point to YPEL3 being a potential tumor suppressor, which upon induction triggers a permanent growth arrest in human tumor and normal cells. Further experiments are underway to determine the precise mechanism through which YPEL3 induces cellular senescence.</p><p>This presentation occurred at the Wright State University Campus-Wide Celebration of Research, Scholarship and Creative Activities on April 16, 2010</p>