title: PARP-1 attenuates Smad-mediated transcription.
abstract: The versatile cytokine transforming growth factor β (TGF-β) regulates cellular growth, differentiation, and migration during embryonic development and adult tissue homeostasis. Activation of TGF-β receptors leads to phosphorylation of Smad2 and Smad3, which oligomerize with Smad4 and accumulate in the nucleus where they recognize gene regulatory regions and orchestrate transcription. Termination of Smad-activated transcription involves Smad dephosphorylation, nuclear export, or ubiquitin-mediated degradation. In an unbiased proteomic screen, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a Smad-interacting partner. PARP-1 dissociates Smad complexes from DNA by ADP-ribosylating Smad3 and Smad4, which attenuates Smad-specific gene responses and TGF-β-induced epithelial-mesenchymal transition. Thus, our results identify ADP-ribosylation of Smad proteins by PARP-1 as a key step in controlling the strength and duration of Smad-mediated transcription.
authors.affiliation: Ludwig Institute for Cancer Research, Uppsala University, Box 595 Biomedical Center, SE-751 24 Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Lönn
authors.forename: Lars P
authors.initials: LP
authors.lastname: van der Heide
authors.forename: Markus
authors.initials: M
authors.lastname: Dahl
authors.forename: Ulf
authors.initials: U
authors.lastname: Hellman
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*; D013379:Substrate Specificity / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D046912:Multiprotein Complexes; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D004247:DNA; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020727:ADP-Ribosylation Factors