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The downregulation of the pro‐apoptotic protein Par‐4 is critical for Ras‐induced survival and tumor progression
Author(s) -
Barradas Marta,
Monjas Alicia,
DiazMeco María T.,
Serrano Manuel,
Moscat Jorge
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.22.6362
Subject(s) - biology , apoptosis , downregulation and upregulation , kinase , cancer research , cell cycle , microbiology and biotechnology , camptothecin , programmed cell death , ectopic expression , cell culture , gene , biochemistry , genetics
Inhibition of apoptosis is an important characteristic of oncogenic transformation. The Par‐4 gene product has recently been shown to be upregulated in cells undergoing apoptotic cell death, and its ectopic expression was shown to be critical in apoptosis. We demonstrate that expression of oncogenic Ras promotes a potent reduction of Par‐4 protein and mRNA levels through a MEK‐dependent pathway. In addition, the expression of permanently active mutants of MEK, Raf‐1 or ζprotein kinase C but not of phosphatidylinositol 3‐kinase (PI 3‐kinase) is sufficient to decrease Par‐4 levels. These effects are independent of p53, p16 and p19, and were detected not only in fibroblast primary cultures but also in NIH 3T3 and HeLa cells, indicating that they are not secondary to Ras actions on cell cycle regulation. Importantly, restoration of Par‐4 levels to normal in Ras‐transformed cells makes these cells sensitive to the pro‐apoptotic actions of tumor necrosis factor‐α under conditions in which PI 3‐kinase is inhibited and also severely impairs colony formation in soft agar and tumor development in nude mice, as well as increases the sensitivity of these tumors to camptothecin. This indicates that the downregulation of Par‐4 by oncogenic Ras is a critical event in tumor progression.