Sp1 phosphorylation regulates apoptosis via extracellular FasL-Fas engagement.
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.
Kavurma
M M
MM
Centre for Thrombosis and Vascular Research, The University of New South Wales, Sydney NSW 2052, Australia.
Santiago
F S
FS
Bonfoco
E
E
Khachigian
L M
LM
D000818:Animals; D017209:Apoptosis; D002166:Camptothecin / Q000494:pharmacology; D002467:Cell Nucleus / Q000648:ultrastructure; D002478:Cells, Cultured; D053938:DNA Fragmentation; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D019014:fas Receptor / Q000378:metabolism*; D000099221:Protein Kinase C zeta
D002166:Camptothecin; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011493:Protein Kinase C; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D019014:fas Receptor; D000099221:Protein Kinase C zeta; C505662:Faslg protein, rat