Survival signal generated by phospholipase D

A critical aspect of tumor progression is the generation of survival signals that overcome default apoptotic programs. Previous data suggested that PLD might contribute to tumorigenesis by overcoming the apoptotic signal induced by stress conditions such as serum deprivation or over-expression of an oncogene. Cellular response to stress is frequently mediated by p53. Therefore we examined the effect of PLD on p53. We found PLD suppresses the p53 response to DNA damage in cells where PLD has been shown to provide a survival signal. Elevated PLD also suppresses DNA damage-induced apoptosis.; The study was extended to human breast cancer cells where p53 is mutated and overexpressed. Surprisingly, the stability of mutant p53 is enhanced by PLD in two breast cancer cell lines---MDA-MB231 and BT549. Also, mutant p53 is required for survival in breast cancer cells that have elevated PLD activity. Moreover, mutant p53 was required for migration and invasion in these two cell lines, implicating a cooperation of elevated PLD activity and gain of function mutation of p53 for survival and metastasis properties of human breast cancer cells.; Another aspect of transformation is suppression of protein phosphatase 2A (MA). Suppression of PP2A by SV40 small t-antigen has been reported to be critical for the transformation of human cells with SV40 early region genes. We therefore examined the effect of PLD on PP2A activity. Elevated PLD activity in the human breast cancer cell line MDA-MB-231 suppressed PP2A activity in an mTOR-dependent manner. Consistent with a critical role for PP2A in PLD survival signals, either SV40 small t-antigen or pharmacological suppression of PP2A restored survival signals lost by suppression of either PLD or mTOR.; The capability of PLD to suppress tumor suppressor p53 and PP2A implicate that PLD can accomplish much of what SV40 early antigen has accomplished. By suppressing wild type p53 and PP2A and promoting the oncogenic function of mutant p53, PLD provides survival signals that contribute to tumorigenesis.