Requirement of NF-κB Activation to Suppress p53-Independent Apoptosis Induced by Oncogenic Ras

Abstract

The ras proto-oncogene is frequently mutated in human tumors and functions to chronically stimulate signal transduction cascades resulting in the synthesis or activation of specific transcription factors, including Ets, c-Myc, c-Jun, and nuclear factor kappa B (NF-kappaB). These Ras-responsive transcription factors are required for transformation, but the mechanisms by which these proteins facilitate oncogenesis have not been fully established. Oncogenic Ras was shown to initiate a p53-independent apoptotic response that was suppressed through the activation of NF-kappaB. These results provide an explanation for the requirement of NF-kappaB for Ras-mediated oncogenesis and provide evidence that Ras-transformed cells are susceptible to apoptosis even if they do not express the p53 tumor-suppressor gene product.

Cooperative activity between HER oncogenes and the tumor suppressor IRF-1 results in apoptosis

“…Overexpression of EGFR in some cells results in proliferation due to a higher amount of survival factors suppressing the apoptotic pathway. Similar data have been described for the protooncogene c-myc (Mayo et al, 1997). Considering the dual activity of the HER oncogenes, IRF-1 might in¯uence the balance of proliferation versus apoptosis.…”

NF-κB is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis

“…Expression levels of endogenous Ras and oncogenic H-Ras proteins were shown to be similar in both cells, ruling out the possibility that the resulting di erence was caused by variations in level of H-Ras protein induction (Figure 4b). In contrast to a previous report (Mayo et al, 1997), induction of oncogenic HRas protein had little e ect on cell viability of RIE(iRas)/DN-IkBa cells. Moreover, consistent with the ®ndings that Ras promotes cell survival rather than cell death in epithelial cells (Cardone et al, 1998;Downward, 1998;Kau man-Zeh et al, 1997;Khwaja et al, 1997;Romashkova and Makarov, 1999), H-Ras induction signi®cantly prevented cell death of RIE(iRas)/DN-IkBa cells upon TNF-a treatment as determined by colonigenic assay (Figure 4c).…”

“…These results suggest that NF-kB activity is not necessary for normal cell growth, but required for Ras-activated abnormal cell proliferation, which contributes to Ras-mediated cell transformation. Earlier studies suggest that NF-kB activation may contribute to cell transformation and tumorigenicity of Ras transformed cells by regulating the expression of genes encoding cell adhesion molecules and by inhibiting transformation-associated cell death (Mayo et al, 1997;Higgins et al, 1993). It has been demonstrated that p65 antisense oligonucleotide inhibited growth and tumorigenicity of variously transformed cell lines including Ras transformed 3T3 cell, presumably by inhibiting cell adhesion processes Narayanan et al, 1993).…”

“…NF-kB has been shown to play an important role in protection from cell death, presumably by regulating the expression of anti-apoptotic genes (Antwerp et al, 1996;Beg et al, 1996;Liu et al, 1996;Wang et al, 1996;Chu et al, 1997;Yamit-Hezi and Dikstein, 1998;You et al, 1997). In light of these observations, it has been reported that Ras activates NF-kB to prevent transformation-mediated cell death and this antiapoptotic activity of NF-kB may be important for Ras-mediated cell transformation and tumorigenesis (Mayo et al, 1997). However, several lines of evidence in this study also suggest an alternative possibility.…”

“…In addition, it has been shown that NF-kB activity is required for the protection of oncogenic Ras-induced cell death, providing a potential mechanism which explains how NF-kB contributes to Ras-induced cellular transformation (Mayo et al, 1997).…”