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Selective Loss of the Transforming Growth Factor-ß Apoptotic Signaling Pathway in Mutant NRP-154 Rat Prostatic Epithelial Cells¹

Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892-5055 [S. L-B., N. S. R., A. Y. H., R. J. L., A. B. R.]; Department of Pathology, Rambam Medical Center, Haifa 31096, Israel [S. L-B., R. L., H. K., T. H.]; Cancer Center and Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106 [D. D.]

Abstract

Retroviral insertional mutagenesis was used to select mutant NRP-154 rat prostate carcinoma cells resistant to transforming growth factor (TGF)-ß-induced cell death. Similar to the parental cells, a mutant clone, M-NRP1, expressed TGF-ß receptors and was still responsive to induction both of direct target genes by TGF-ß and of apoptosis by staurosporine or okadaic acid. In contrast, indicators of cell growth, strongly suppressed by TGF-ß in the parental cells, were unaffected in M-NRP1 cells. M-NRP1 cells overexpress the antiapoptotic protein, Bcl-xL, and show dysregulated expression and localization of a protein related to a novel human septin, ARTS (designation of apoptotic response to TGF-ß signals), cloned by homology to an exonic sequence flanked by the viral long terminal repeats in M-NRP1 cells and shown to make cells competent to undergo apoptosis in response to TGF-ß. We propose that ARTS might operate within the same apoptotic pathway as Bcl-xL and that M-NRP1 cells could serve as a useful model for characterization of this pathway.

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