p53 regulation by post-translational modification and nuclear retention in response to diverse stresses

Abstract

p53 activation by diverse stresses involves post-translational modi®cations that alter its structure and result in its nuclear accumulation. We will discuss several unresolved topics regarding p53 regulation which are currently under investigation. DNA damage is perhaps the best-studied stress which activates p53, and recent data implicate phosphorylation at N-terminal serine residues as critical in this process. We discuss recent data regarding the potential kinases which modify p53 and the possible role of the resulting phosphorylation events. By contrast, much less is understood about agents which disrupt the mitotic spindle. The cell cycle phase, induction signal, and biochemical mechanism of the reversible arrest induced by microtubule disruption are currently under investigation. Finally, a key event in response to any genotoxic stress is the accumulation of p53 in the nucleus. The factors which determine the steady state level of p53 are starting to be elucidated, but the mechanisms responsible for nuclear accumulation and nuclear export remain controversial. We discuss new studies revealing a mechanism for nuclear retention of p53, and the potential contributions of MDM2 to this process.

Isolation and characterization of sixteen novel p53 response genes

“…Treatment with a number of drugs a ecting the integrity of the cytoskeleton, either at the level of microtubules (vinblastine, nocodazol, vincristine, colchicine and taxol Tishler et al (1995)), or at the level of actin ®bres (cytochalasin; Rubtsova et al (1998)), and heat shock (Li et al, 1999)), results in a stabilized and activated p53. This type of observation prompted Wahl and colleagues in a recent review to hypothesize that p53 or a protein(s) upstream of p53 senses microtubule disarray (Jimenez et al, 1999). We propose that this theme can be enlarged to include the status of actin ®bres as well.…”

“…Activation of the p53 protein is observed following stress situations, such as DNA damage (Levine, 1997), oxidative stress (Renzing et al, 1996), microtubule disrupting agents (Jimenez et al, 1999), and hypoxia (Graeber et al, 1996). Elevated p53 activity leads to cell cycle arrest or apoptosis, depending on the cell type and the intensity of the stimulus (Amundson et al, 1998;Levine, 1997).…”

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

“…12 The chemotherapeutic drugs doxorubicin (Adriamycin) and 5-FU stabilize and activate p53 in HCT116 cells. 10 To study whether resveratrol affects p53 stability and expression of p53 target genes, HCT116 cultures were exposed to 100 M resveratrol or, as a control, to 375 M 5-FU for 3, 6 or 12 hr.…”

“…7,8 The presence of the functional wild-type form of the p53 tumor suppressor correlates with the sensitivity of mouse tumors and at least some human tumors to therapeutic agents. 9 -11 p53 is stabilized and activated as a transcription factor in response to a variety of cellular stresses, 12 the result being either cell-cycle arrest, mostly through transcriptional activation of the p21 WAF/Cip1 inhibitor of cyclin-dependent kinases, or apoptosis, depending on the cell context. Apoptosis often involves changes to mitochondria.…”

p53 activation in response to microtubule disruption is mediated by integrin-Erk signaling

“…into growth arrest or apoptosis (reviewed in Giaccia and Kastan, 1998;Gottlieb and Oren, 1996;Jimenez et al, 1999;Sherr, 1998). In this way the p53 controls immediate elimination of genetically damaged and potentially dangerous cells.…”