title: Smad-mediated transcription is required for transforming growth factor-beta 1-induced p57(Kip2) proteolysis in osteoblastic cells.
abstract: Cyclin-dependent kinase inhibitory proteins (CKIs) are negative regulators of the cell cycle. Of all CKIs, only p57(Kip2) plays an essential role(s) that other CKIs cannot compensate for in embryonic development. Recently, we found that p57(Kip2) is degraded through the ubiquitin-proteasome pathway in osteoblastic cells stimulated to proliferation by transforming growth factor (TGF)-beta1 (Urano, T., Yashiroda, H., Muraoka, M., Tanaka, K., Hosoi, T., Inoue, S., Ouchi, Y., and Toyoshima, H. (1999) J. Biol. Chem. 274, 12197-12200). We report here that TGF-beta1-induced p57(Kip2) proteolysis is mediated through transcription by the Smad pathway. When the constitutively active form of the TGF-beta type I receptor ALK-5(TD) was ectopically expressed in osteoblastic cells, p57(Kip2) that had been accumulated by serum starvation causing the cell-cycle arrest was rapidly degraded in a manner analogous to TGF-beta1 stimulation. Moreover, Smad2 or Smad3 with Smad4 enhanced the proteolytic pathway of p57(Kip2). The degradation of p57(Kip2) evoked by TGF-beta1 was blocked by forced expression of an inhibitory Smad called Smad7 or by the addition of actinomycin D or alpha-amanitin. These results indicate that accelerated degradation of p57(Kip2) by TGF-beta1/Smad signaling is mediated through a newly synthesized factor(s) that modifies p57(Kip2) or the ubiquitin-proteasome pathway.
authors.affiliation: Department of Molecular Oncology, and the Department of Tumor Biochemistry, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nishimori
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Chiba
authors.forename: M
authors.initials: M
authors.lastname: Fujii
authors.forename: T
authors.initials: T
authors.lastname: Imamura
authors.forename: K
authors.initials: K
authors.lastname: Miyazono
authors.forename: T
authors.initials: T
authors.lastname: Ogasawara
authors.forename: H
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: T
authors.initials: T
authors.lastname: Igarashi
authors.forename: T
authors.initials: T
authors.lastname: Fujita
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Toyoshima
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D009687:Nuclear Proteins; D016212:Transforming Growth Factor beta; D018844:Cyclin-Dependent Kinases