Does the form of cellular stress influence the p53 response?
The nature of the upstream signaling pathways may influence p53 post-translational modifications and consequently, this could impact whether p53 affects cell proliferation or survival. Detailed genetic and biochemical analyses demonstrated that DNA-damaging events trigger p53 activation through the engagement of ATM, ATR and Chk-1 and 2.27 Phosphorylation of p53 by these protein kinases is required to release p53 efficiently from its negative regulator Mdm2,28 thus stabilizing p53 and activating its tumor suppressor functions. By contrast, hyperproliferative signals emanating from activated ras and myc oncogenes activate p53 indirectly through the induction of p19ARF, an alternative reading frame gene product of the INK4a locus,29 and this occurs independently of DNA damage and the ATM/ATR pathway. It is not clear how ARF is regulated by inappropriate cell growth, but when expressed at sufficient levels, ARF activates p53 by binding Mdm2, thereby blocking its E3-ubiquitin ligase activi
