Oncogenic Ras sensitizes cells to apoptosis by Par-4

Certain mutations in the mammalian ras gene are oncogenic and are often det ected in human cancers. Oncogenic Bas induces the transcription activity of NF-KB that confers cell survival. Oncogenic Ras also down-modulates the ex pression of Par-4, a transcriptional repressor protein, that is essential b ut not sufficient on its own to induce apoptosis, Were we show that reintro duction of Par-4 by transient transfection leads to apoptosis in cells expr essing oncogenic Ras but not in those that lack oncogenic Ras expression. P ar-4 abrogates oncogenic Ras-inducible NF-KB transcription activity but doe s not interfere with cytoplasmic activation, or the DNA binding activity, o f NF-KB. Because abrogation of NF-KB transcription activity is sufficient t o cause apoptosis in cells expressing oncogenic Was, our findings identify Par-4 as a novel example of a pro-apoptotic protein that selectively inhibi ts oncogenic Ras-dependent NF-kappa B function at the transcription level a nd suggest a mechanism by which Par-4 expression may selectively induce apo ptosis in oncogenic Ras-expressing cells.