Oncogenic Ras sensitizes cells to apoptosis by Par-4.
Certain mutations in the mammalian ras gene are oncogenic and are often detected in human cancers. Oncogenic Ras induces the transcription activity of NF-kappaB that confers cell survival. Oncogenic Ras also down-modulates the expression of Par-4, a transcriptional repressor protein, that is essential but not sufficient on its own to induce apoptosis. Here we show that reintroduction of Par-4 by transient transfection leads to apoptosis in cells expressing oncogenic Ras but not in those that lack oncogenic Ras expression. Par-4 abrogates oncogenic Ras-inducible NF-kappaB transcription activity but does not interfere with cytoplasmic activation, or the DNA binding activity, of NF-kappaB. Because abrogation of NF-kappaB transcription activity is sufficient to cause apoptosis in cells expressing oncogenic Ras, our findings identify Par-4 as a novel example of a pro-apoptotic protein that selectively inhibits oncogenic Ras-dependent NF-kappaB function at the transcription level and suggest a mechanism by which Par-4 expression may selectively induce apoptosis in oncogenic Ras-expressing cells.
Nalca
A
A
Department of Surgery, Division of Urology, University of Kentucky, Lexington, Kentucky 40536, USA.
Qiu
S G
SG
El-Guendy
N
N
Krishnan
S
S
Rangnekar
V M
VM
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008025:Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D014158:Transcription, Genetic
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C101296:prostate apoptosis response-4 protein; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D019908:Proto-Oncogene Proteins c-raf; D015689:Oncogene Protein p21(ras); D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases