Alternative effects of RAS and RAF oncogenes on the proliferation and apoptosis of factor-dependent FDC-P1 cells

Despite the fact that RAF-1 lies immediately downstream of p21RAS in the MA P kinase-signalling cascade, recent evidence in non-haematopoietic environm ents suggest that RAS and RAF can transduce signals through alternative pat hways specific to a particular cell type. Since mutational activation of RA S occurs at high frequency in human leukaemia, we have investigated the con tribution of signalling from mutant RAF in mediating the transforming effec ts of the N-RAS oncogene in the growth factor-dependent cell line, FDC-P1. Independent activation of N-RAS extended the period of exponential growth l eading to an increased saturating density under optimal growth conditions. Under conditions of growth factor withdrawal, cells expressing mutant RAS, but not control cells, demonstrated protection against apoptotic: death. Al though RAF promoted cell proliferation in a similar manner to that observed in FDCP-RAS cells, expression of mutant RAF was not as effective at protec ting these cells against apoptotic death following growth factor withdrawal . The results suggest that RAS utilises RAF-dependent signals in promoting the proliferation of FDC-P1 cells but the anti-apoptotic effects of this on cogene are mediated through a RAF- and BCL-2-independent pathway. (C) 1999 Elsevier Science Ltd. All rights reserved.