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J. Biol. Chem. 276 (7): 4964-4971

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Sp1 Phosphorylation Regulates Apoptosis via Extracellular FasL-Fas Engagement*

Mary M. KavurmaDagger , Fernando S. SantiagoDagger , Emanuela Bonfoco§, and Levon M. KhachigianDagger ||

From the Dagger  Centre for Thrombosis and Vascular Research, The University of New South Wales, Sydney NSW 2052, Australia and the § Scripps Research Institute, La Jolla, California 92037

Apoptosis of smooth muscle cells (SMC) in atherosclerotic vessels can destabilize the atheromatus plaque and result in rupture, thrombosis, and sudden death. In efforts to understand the molecular processes regulating apoptosis in this cell type, we have defined a novel mechanism involving the ubiquitously expressed transcription factor Sp1. Subtypes of SMC expressing abundant levels of Sp1 produce the death agonist, Fas ligand (FasL) and undergo greater spontaneous apoptosis. Sp1 activates the FasL promoter via a distinct nucleotide recognition element whose integrity is crucial for inducible expression. Inducible FasL promoter activation is also inhibited by a dominant-negative form of Sp1. Increased SMC apoptosis is preceded by Sp1 phosphorylation, increased FasL transcription, and the autocrine/paracrine engagement of FasL with its cell-surface receptor, Fas. Inducible FasL transcription and apoptosis are blocked by dominant-negative protein kinase C-zeta , whose wild-type counterpart phosphorylates Sp1. Thus, Sp1 phosphorylation is a proapoptotic transcriptional event in vascular SMC and, given the wide distribution of this housekeeping transcription factor, may be a common regulatory theme in apoptotic signal transduction.

* This work was supported in part by grants from the Australian Research Council (to L. M. K.), National Health and Medical Research Council of Australia (NHMRC) (to L. M. K.), and an NSW Department of Health Infrastructure grant to the Centre for Thrombosis and Vascular Research.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Research Fellow of the NHMRC.

|| To whom correspondence should be addressed. Tel.: 61-2-9385 2537; Fax: 61-2-9385 1389; E-mail: l.Khachigian@unsw.edu.au.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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