83719

YPEL3

-;yippee-like 3 (Drosophila);YPEL3;yippee-like 3 (Drosophila)

protein yippee-like 3

16p11.2

protein-coding

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). Although both processes require a functional p53 signaling pathway, relevant downstream p53 targets 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 in which p53 was reactivated in MCF7 cells, we discovered that Yippee-like-3 (YPEL3), a member of a recently discovered family of putative zinc finger motif coding genes consisting of YPEL1-5, is a p53-regulated gene. YPEL3 expression induced by DNA damage leads to p53 recruitment to a cis-acting DNA response element located near the human YPEL3 promoter. Physiologic induction of YPEL3 results in a substantial decrease in cell viability associated with an increase in cellular senescence. Through the use of RNAi and H-ras induction of cellular senescence, we show that YPEL3 activates cellular senescence downstream of p53. Consistent with its growth suppressive activity, YPEL3 gene expression is repressed in ovarian tumor samples. One mechanism of YPEL3 downregulation in ovarian tumor cell lines seems to be hypermethylation of a CpG island upstream of the YPEL3 promoter. We believe these findings point to YPEL3 being a novel tumor suppressor, which upon induction triggers a permanent growth arrest in human tumor and normal cells.

Yippee-like 3 (YPEL3) was reported in 2004 as one of five family members of the Yippee protein with conservation in species down to slime molds. While reports of other YPEL family members have surfaced our laboratory was the first to report that YPEL3 is induced by the p53 tumor suppressor. Furthermore we demonstrated that YPEL3 is growth suppressive, triggering cellular senescence in human cell lines and is down-regulated in several human tumors. Studies with mouse YPEL3, originally named small unstable apoptotic protein (SUAP), confirmed that the gene encodes a growth suppressive highly unstable protein. In this review we show that transcriptionally active forms of p73 and p63, family members of p53, can transactivate the human YPEL3 gene. While there are several reported YPEL3 transcripts and potentially 2 protein isoforms, no clear protein structure has been reported. As evidence mounts that YPEL3 is a tumor suppressor gene, studies aimed at understanding its biological function, regulation of gene expression and impact on tumorigenesis will help.