The downregulation of the pro-apoptotic protein Par-4 is critical for Ras-induced survival and tumor progression.
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 zetaprotein 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-alpha 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.
Barradas
M
M
Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Universidad Autónoma, Canto Blanco, Madrid, Spain.
Monjas
A
A
Diaz-Meco
M T
MT
Serrano
M
M
Moscat
J
J
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D005260:Female; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D016158:Genes, p53; D011905:Genes, ras; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008868:Microtubule Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011493:Protein Kinase C / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D050777:Stathmin; D014183:Transplantation, Heterologous; D018631:ras Proteins / Q000378:metabolism*; D000099221:Protein Kinase C zeta
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D008868:Microtubule Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D016283:Proto-Oncogene Proteins p21(ras); D050777:Stathmin; D018631:ras Proteins; D000099221:Protein Kinase C zeta; C493995:STMN1 protein, human; C493994:Stmn1 protein, mouse; C101296:prostate apoptosis response-4 protein; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse; C501009:HRAS protein, human