The downregulation of the pro-apoptotic protein Par-4 is critical for Ras-induced survival and tumor progression.

Publisher: Wiley Blackwell Country of Publication: England NLM ID: 8208664 Publication Model: Print Cited Medium: Print ISSN: 0261-4189 (Print) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE

Publication: 2014- : London : Wiley Blackwell
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-

Cell Transformation, Neoplastic* ; Gene Expression Regulation, Neoplastic* ; Genes, ras* ; Intracellular Signaling Peptides and Proteins* ; MAP Kinase Kinase Kinase 1* ; Microtubule Proteins* ; Protein Serine-Threonine Kinases*; Apoptosis/*physiology ; Carrier Proteins/*genetics ; Carrier Proteins/*metabolism ; Cell Survival/*physiology ; Proto-Oncogene Proteins p21(ras)/*metabolism ; ras Proteins/*metabolism; 3T3 Cells ; Animals ; Apoptosis Regulatory Proteins ; Cell Cycle ; Cell Line ; Cell Line, Transformed ; Female ; Fibroblasts ; Genes, p16 ; Genes, p53 ; HeLa Cells ; Humans ; MAP Kinase Kinase Kinases/genetics ; Mice ; Mice, Knockout ; Mice, Nude ; Phosphatidylinositol 3-Kinases/genetics ; Phosphoproteins/deficiency ; Phosphoproteins/genetics ; Phosphoproteins/physiology ; Protein Kinase C/genetics ; Proto-Oncogene Proteins c-raf/genetics ; Stathmin ; Transplantation, Heterologous

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.

0 (Apoptosis Regulatory Proteins)
0 (Carrier Proteins)
0 (Intracellular Signaling Peptides and Proteins)
0 (Microtubule Proteins)
0 (Phosphoproteins)
0 (STMN1 protein, human)
0 (Stathmin)
0 (Stmn1 protein, mouse)
0 (prostate apoptosis response-4 protein)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
EC 2.7.11.1 (protein kinase C zeta)
EC 2.7.11.13 (Protein Kinase C)
EC 2.7.11.25 (MAP Kinase Kinase Kinase 1)
EC 2.7.11.25 (MAP Kinase Kinase Kinases)
EC 2.7.11.25 (MAP3K1 protein, human)
EC 2.7.11.25 (Map3k1 protein, mouse)
EC 3.6.5.2 (HRAS protein, human)
EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
EC 3.6.5.2 (ras Proteins)

Date Created: 19991124 Date Completed: 20000120 Latest Revision: 20211203

20221213

PMC1171699

10.1093/emboj/18.22.6362

10562548