Regulation of p53 stability by Mdm2

Abstract

The tumour-suppressor p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Stabilization of the protein in response to an activating signal, such as DNA damage, results in a rapid rise in p53 levels and subsequent inhibition of cell growth. Tight regulation of p53 function is critical for normal cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein. Mdm2 inhibits p53 cell-cycle arrest and apoptic functions and we show here that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation. Endogenous levels of Mdm2 are sufficient to regulate p53 stability, and overexpression of Mdm2 can reduce the amount of endogenous p53. Because mdm2 is transcriptionally activated by p53, this degradative pathway may contribute to the maintenance of low p53 concentrations in normal cells. Furthermore, mechanisms regulating the Mdm2-induced degradation of p53 may play a role in controlling the extent and duration of the p53 response.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…MDM2 inhibits the transcriptional activity of p53 by blocking the association of the transactivation domain of p53 with the transcriptional machinery Oliner et al, 1993). However, MDM2 also plays a central role in the regulation of p53 levels in the cells since this oncoprotein targets p53 for rapid degradation Kubbutat et al, 1997), implying an autoregulatory feedback between p53 and MDM2. This regulation may allow cells to recover from G1 arrest.…”

High prognostic significance of Mdm2/p53 co-overexpression in soft tissue sarcomas of the extremities

“…These ®ndings are unexpected, because overexpression of Mdm2 can substantially decrease wild-type and mutant p53 expression (Haupt et al, 1997;Kubbutat et al, 1997). But modi®cation of either Mdm2 or p53, such as by phosphorylation, may protect from Mdm2-induced p53 degradation (Kubbutat et al, 1997).…”

“…But modi®cation of either Mdm2 or p53, such as by phosphorylation, may protect from Mdm2-induced p53 degradation (Kubbutat et al, 1997). In p53 the N-terminal region with a transcriptional activation domain is required for p53-dependent apoptosis (Chen et al, 1996).…”

“…A way to regulate p53 function is interaction with Mdm2, since Mdm2 can regulate stability of p53 via degradation (Haupt et al, 1997;Kubbutat et al, 1997). Thus, it can inhibit p53 dependent cell-cycle arrest or apoptosis (Haupt et al, 1993;Chen et al, 1996).…”

Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

“…p19 ARF associates with and inhibits Mdm2 (Kamijo et al, 1998;Pomerantz et al, 1998;Stott et al, 1998;Zhang et al, 1998), which acts in a feedback loop to antagonize p53 function by direct binding (Barak et al, 1993;Wu et al, 1993). Mdm2 association with p53 inhibits p53 transcriptional activity (Momand et al, 1992;Oliner et al, 1993), induces p53 ubiquitination (Haupt et al, 1997;Honda et al, 1997;Kubbutat et al, 1997) and accelerates p53 nuclear export and its degradation in cytoplasmic proteosomes (Roth et al, 1998). Consistent with these ®ndings, the E1A-induced apoptosis appears to be dependent on p53-mediated pathways (Debbas and White, 1993;Lowe and Ruley, 1993;Querido et al, 1997;Samuelson and Lowe, 1997).…”