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.2011 Oct 15;10(20):3515-8.
doi: 10.4161/cc.10.20.17789. Epub 2011 Oct 15.

MG132 inhibition of proteasome blocks apoptosis induced by severe DNA damage

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MG132 inhibition of proteasome blocks apoptosis induced by severe DNA damage

Ling Zhang et al. Cell Cycle..

Abstract

The 26S proteasome, a multicatalytic enzyme complex, is the main intracellular proteolytic system involved in the degradation of ubiquitinated proteins. The ability of proteasome inhibitors to induce apoptosis has been exploited in the recent development of chemotherapeutic agents. Here, we show that inhibition of proteasome by MG132 blocks DNA damage-induced apoptosis. Blockage of apoptosis by MG132 correlates with p53 stabilization and upregulation of p21/WAF1, a p53 transcriptional target. Surprisingly, in the absence of MG132, robust apoptosis induced by a high dose of UV irradiation correlate with rapid p53 degradation. This is in sharp contrast to p53 stabilization when cells were exposed to lower levels of UV irradiation. Our findings highlight a scenario in which severe UV damage can induce rapid p53 degradation by the proteasome. Importantly, these data suggest that the 26S proteasome plays a key role in promoting apoptosis induced by high doses of UV irradiation.

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Figures

Figure 1
Figure 1
(A) TUNEL assay showing that MG132 inhibited a high dose of UV irradiation induced apoptosis. HeLa cells were treated with MG132 (5 µM) or DMSO for 60 min before UV treatment. A UV-C crosslinker was used to expose cells at a dose of 100 J/m2. TUNEL assay was performed using the In Situ Cell Death Detection Kit (Roche).
Figure 2
Figure 2
Protein gel blot showing a high dose of UV irradiation induced PARP cleavage and its inhibition by MG132. HeLa cells were treated with MG132 (5 µM) or DMSO for 60 min before UV treatment. Cell lysates were collected for protein gel blot analysis using an antibody specific for the cleaved form of PARP as described in Materials and Methods.
Figure 3
Figure 3
Protein gel blot showing increased p53 levels after MG132 treatment and p53 stabilization after a low-dose of UV irradiation. HeLa cells were treated with MG132 (5 µM) or DMSO for 60 min before UV treatment. Cell lysates were collected for protein gel blot analysis as described in Materials and Methods.
Figure 4
Figure 4
MG132 treatment inhibited p53 degradation and led to p21 upregulation. HeLa cells were treated with MG132 (5 µM) or DMSO for 60 min before UV treatment. Cell lysates were collected for protein gel blot analysis as described in Materials and Methods.
Figure 5
Figure 5
(A) The central role of p53 in DNA damage signaling. DNA damage signal transduction leads to p53 phosphorylation and disruption of the p53-ubiquitin E3 ligase interaction. Activated p53 acts as a transcription factor to promote cell cycle arrest or apoptosis by regulating gene expression. (B) A model depicting MG132 inhibition of p53-independent apoptosis after severe DNA damage. Rapid degradation of p53 (or an anti-apoptotic factor X) by the proteasome will ensure swift activation of apoptosis in a p53-independent manner after severe UV damage. Apoptosis will be inhibited by factor X/or p53 when proteasomal removal of these factors is blocked by MG132.
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