Enforced expression of PPP1R13L increases tumorigenesis and invasion through p53-dependent and p53-independent mechanisms.

Abstract

PPP1R13L was initially identified as a protein that binds to the NF-[kappa]B subunit p65/RelA and inhibits its transcriptional activity. It also binds p53 and inhibits its action. One set of experimental findings based on over-expression of PPP1R13L indicates that PPP1R13L blocks apoptosis. Another set of experiments, based on endogenous production of PPP1R13L, suggests that the protein may sometimes be pro-apoptotic. We have used primary mouse embryonic fibroblasts (MEFs), dually transformed by H-ras and Adenovirus E1A and differing in their p53 status, to explore the effects of PPP1R13L over-expression, thus examining the ability of PPP1R13L to act as an oncoprotein. We found that over-expression of PPP1R13L strongly accelerated tumor formation by ras/E1A and also resulted in an increased metastatic potential of the tumors. PPP1R13L over-expressing cells were depleted for both p53 and active p65/RelA and we found that both p53 dependent and independent apoptosis pathways were regulated by PPP1R13L. Finally, studies with the proteasome inhibitor MG132 revealed that over-expression of PPP1R13L causes faster p53 degradation, a likely explanation for the depletion of p53. Taken together, our results show that increased levels of PPP1R13L can increase tumorigenesis and furthermore pinpoint PPP1R13L as a gene that influences metastasis.