Sp1 phosphorylation regulates apoptosis via extracellular FsasL-Fas engagement

Apoptosis of smooth muscle cells (SMC) in atherosclerotic vessels can desta bilize the atheromatus plaque and result in rupture, thrombosis, and sudden death. In efforts to understand the molecular processes regulating apoptos is in this cell type, we have defined a novel mechanism involving the ubiqu itously expressed transcription factor Sp1. Subtypes of SMC expressing abun dant levels of Spl produce the death agonist, Fas ligand (FasL) and undergo greater spontaneous apoptosis, Sp1 activates the FasL promoter via a disti nct nucleotide recognition element whose integrity is crucial for inducible expression. Inducible FasL promoter activation is also inhibited by a domi nant-negative form of Sp1, Increased SMC apoptosis is preceded by Sp1 phosp horylation, increased FasL transcription, and the autocrine/ paracrine enga gement of FasL with its cell-surface receptor, Fas, Inducible FasL transcri ption 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 re gulatory theme in apoptotic signal transduction.