MG132 inhibition of proteasome blocks apoptosis induced by severe DNA damage.
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.
Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Ling
L
Zhang
Jennifer J
JJ
Hu
Feng
F
Gong
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D006367:HeLa Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D007976:Leupeptins / Q000494:pharmacology*; D008954:Models, Biological; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D055550:Protein Stability / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007976:Leupeptins; D061988:Proteasome Inhibitors; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde