EGF receptor activity modulates apoptosis induced by inhibition of the proteasome of vascular smooth muscle cells.
The observation that intracellular protein turnover rates participate directly in cell viability led to the development and clinical use of potent proteasome inhibitors. This study determined that the mechanism of apoptosis that is induced by inhibition of the proteasome of vascular smooth muscle cells (VSMC) was related to the intracellular accumulation of Bad, a BH3-only member of the Bcl-2 family of apoptosis regulators. Experiments confirmed that the apoptotic process was mitochondria- and caspase-dependent. Ubiquitination and accumulation of Bad in VSMC followed inhibition of the proteasome, and depletion of Bad using RNA interference prevented apoptosis that was induced by proteasome inhibition with PS-341. EGF receptor (EGFR) activation produced posttranslational modifications of Bad, providing the pro-survival signals that prevented apoptosis of smooth muscle cells during proteasome inhibition. Antagonists of the EGFR potentiated the apoptotic rate. In summary, the activities of the EGFR and the proteasome focused on Bad and the intrinsic apoptotic pathway and were involved integrally in determining viability of VSMC. These findings might prove useful in the management of diseases in which proliferation of vascular smooth muscle cells plays a central role.
Ying
Wei-Zhong
WZ
Division of Nephrology/Department of Medicine, niversity of Alabama at Birmingham, Birmingham, AL 35294-0007, USA.
Zhang
Huang-Ge
HG
Sanders
Paul W
PW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational; D011719:Pyrazines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D051025:bcl-Associated Death Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C494821:Bad protein, rat; D001897:Boronic Acids; C509204:PD168393; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011799:Quinazolines; D051025:bcl-Associated Death Protein; D000069286:Bortezomib; D066246:ErbB Receptors; D020169:Caspases