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Mol Cell Biol, February 1998, p. 839-845, Vol. 18, No. 2
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Activation of Protein Kinase C Triggers Its Ubiquitination and Degradationdagger

Zhimin Lu,1 David Liu,2 Armand Hornia,1 Wayne Devonish,1 Michele Pagano,2 and David A. Foster1,*

Department of Biological Sciences, Hunter College and the Graduate School of the City University of New York, New York, New York 10021,1 and Department of Pathology, New York University Medical Center, New York, New York 100162

Received 13 August 1997/Returned for modification 25 September 1997/Accepted 20 October 1997

Treatment of cells with tumor-promoting phorbol esters results in the activation but then depletion of phorbol ester-responsive protein kinase C (PKC) isoforms. The ubiquitin-proteasome pathway has been implicated in regulating the levels of many cellular proteins, including those involved in cell cycle control. We report here that in 3Y1 rat fibroblasts, proteasome inhibitors prevent the depletion of PKC isoforms alpha , delta , and varepsilon  in response to the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Proteasome inhibitors also blocked the tumor-promoting effects of TPA on 3Y1 cells overexpressing c-Src, which results from the depletion of PKC delta . Consistent with the involvement of the ubiquitin-proteasome pathway in the degradation of PKC isoforms, ubiquitinated PKC alpha , delta , and varepsilon  were detected within 30 min of TPA treatment. Diacylglycerol, the physiological activator of PKC, also stimulated ubiquitination and degradation of PKC, suggesting that ubiquitination is a physiological response to PKC activation. Compounds that inhibit activation of PKC prevented both TPA- and diacylglycerol-induced PKC depletion and ubiquitination. Moreover, a kinase-dead ATP-binding mutant of PKC alpha  could not be depleted by TPA treatment. These data are consistent with a suicide model whereby activation of PKC triggers its own degradation via the ubiquitin-proteasome pathway.

* Corresponding author. Mailing address: Department of Biological Sciences, Hunter College and the Graduate School of the City University of New York, 695 Park Ave., New York, NY 10021. Phone: (212) 772-4075. Fax: (212) 772-5227. E-mail: foster{at}genectr.hunter.cuny.edu.

dagger This paper is dedicated to Erwin Fleissner on the occasion of his retirement as the dean of sciences and mathematics at Hunter College.




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