Opposing Effects of Ras on p53

Abstract

Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Here, we show that the mdm2 gene is also regulated by the Ras-driven Raf/MEK/MAP kinase pathway, in a p53-independent manner. Mdm2 induced by activated Raf degrades p53 in the absence of the Mdm2 inhibitor p19ARF. This regulatory pathway accounts for the observation that cells transformed by oncogenic Ras are more resistant to p53-dependent apoptosis following exposure to DNA damage. Activation of the Ras-induced Raf/MEK/MAP kinase may therefore play a key role in suppressing p53 during tumor development and treatment. In primary cells, Raf also activates the Mdm2 inhibitor p19ARF. Levels of p53 are therefore determined by opposing effects of Raf-induced p19ARF and Mdm2.

GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis

“…The hdm2-P2 promoter is also regulated by factors other than p53, the extent of this p53-independent transcription again being an important regulator of cellular p53 activity (Ries et al, 2000). T47D breast cancer cells, despite expressing functionally inactive mutant p53, express similar levels of the hdm2-P2 transcript to wild-type p53 expressing MCF-7 cells (Phelps et al, 2003).…”

“…This response to p53 is the key in regulating the duration of the p53-response to genotoxic stress (Lev Bar-Or et al, 2000). A number of other signalling pathways and transcription factors also impinge upon the activity of the p53-Hdm2 module via the regulation of the activity of the P2-promoter, including thyroid hormone receptors (Qi et al, 1999), HEY1 and HES1 transcriptional repressors (Huang et al, 2004), MYCN (Slack et al, 2005) and Ras-Raf-MEK-ERK signalling (Ries et al, 2000;Phelps et al, 2003Phelps et al, , 2005. Hdm2 protein synthesis is also subject to post-transcriptional control; the export of hdm2 message from the nucleus to the cytoplasm is controlled by cellular MEK activity (Phelps et al, 2005), and hdm2 mRNA translation rates are elevated in some cancer cells (Landers et al, 1997;Trotta et al, 2003).…”

Oncogenes in melanoma

“…In melanoma, overexpression of HDM2 has been observed in the absence of amplification (Polsky et al, 2001). As transcription of HDM2 is controlled by both p53 and factors upregulated by growth factor receptor signaling (Ries et al, 2000), it was initially unclear whether HDM2 was acting as an oncogene in melanoma, or a marker of p53 activation. More recently, overexpression of HDM2 was shown to correlate with improved clinical outcomes in melanoma patients, independent of tumor thickness, the most important prognostic marker in localized disease (Polsky et al, 2002 #782).…”

Ha-rasval12 induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-rasval12-transformed cells

“…The Ha-ras val12 oncogene, for example, induces growth arrest and senescence in primary cell cultures (Serrano et al, 1997), although in established cell lines it induces oncogenesis (Marshall, 1996;Lloyd, 1998;Hanahan and Weinberg, 2000). In primary cultures, Ras evokes growth arrest by activating proteins such as p53, p21, p16INK4A, CDK4 and p19ARF (Serrano et al, 1997;Ries et al, 2000;Lazarov et al, 2002). Development of an oncogenic phenotype in primary cultures may occur upon inactivation of one of them (Serrano et al, 1997;Sahai et al, 2001).…”