本學期最後一篇
Proteasome activator PA28r regulates p53 by enhancing its MDM2-mediated
degradation
The EMBO journal 2008
Abstract:
Downregulation of p53 by MDM2-mediated proteasomal degradation makes
cells resistant to apoptosis. The MDM2-p53 interaction is well characterized,
but the mechanisms that regulate the interaction are not well understood.
Here, we show that PA28r, a proteasome activator that inhibits apoptosis
and promotes cell cycle progression through unknown mechanisms, exerts an
effect as a cofactor in the MDM2-p53 interaction. The polymer form of PA28r
interacts with both MDM2 and p53 proteins and facilitates their physical
interaction. This promotes ubiquitination and MDM2-dependent proteasomal
degradation of p53, limiting its accumulation and resulting in inhibited
apoptosis after DNA damage.
Elimination of endogenous PA28r in human cancer cells abrogates MDM2-mediated
p53 degradation, increases the activity of p53, and enhances apoptosis. These
findings reveal the mechanism by which PA28r affects apoptosis and prolifera-
tion. Manipulation if the level of PA28r, an approach that would regulate the
cellular content of p53, may improve the efficacy of current cancer therapies.
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