title: Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21(WAF1/Cip1).
abstract: Transforming growth factor-beta (TGF-beta) inhibits epithelial cell growth, in part via transcriptional induction of the cell cycle inhibitor p21(WAF1/Cip1) (p21). We show that bone morphogenetic protein (BMP)-7 induces higher p21 expression than TGF-beta1 in various epithelial cells. Despite this, BMP-7 only weakly suppresses epithelial cell proliferation, as Id2, a cell cycle-promoting factor, becomes concomitantly induced by BMP-7. Signaling studies with all type I receptors of the TGF-beta superfamily show that BMP receptors induce higher p21 expression than TGF-beta/activin receptors. Smad4 is essential for p21 regulation by all receptor pathways. Based on the previously known ability of c-Myc to block p21 expression and epithelial growth arrest in response to TGF-beta1, we demonstrate that ectopic c-Myc expression can abrogate Smad-mediated p21 induction by all TGF-beta and BMP receptors. Furthermore, p21 induction by all receptor pathways can be blocked by the natural inhibitors of the TGF-beta superfamily. Smad7 inhibits all pathways whereas Smad6 selectively inhibits the BMP pathways. The observed pathway specificity reflects the efficiency by which BMP Smads, compared to TGF-beta Smads, transactivate the p21 promoter. In addition, BMP-specific Smads, Smad1, Smad5, and especially Smad8, induce endogenous p21 mRNA and protein levels, while they fail to induce epithelial growth inhibition when compared to TGF-beta receptor-phosphorylated Smads (R-Smads), Smad2 and Smad3. Thus, p21 is a common target of all TGF-beta superfamily pathways. However, the ability of TGF-beta superfamily members to induce cell growth arrest depends on the regulation of additional gene targets.
authors.affiliation: Ludwig Institute for Cancer Research, Uppsala, Sweden.
authors.forename: Katerina
authors.initials: K
authors.lastname: Pardali
authors.forename: Marcin
authors.initials: M
authors.lastname: Kowanetz
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
mesh_terms: D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D051902:Smad5 Protein; D051906:Smad7 Protein; D051904:Smad8 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C489427:MYC protein, human; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; C497797:SMAD5 protein, human; C497806:SMAD7 protein, human; C107514:SMAD9 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D051902:Smad5 Protein; D051906:Smad7 Protein; D051904:Smad8 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1