title: Phosphorylation of the anaphase-promoting complex/Cdc27 is involved in TGF-beta signaling.
abstract: Loss of TGF-β-induced growth inhibition is a hallmark of many human tumors. Previous studies implied that activation of the anaphase-promoting complex (APC/cyclosome) is involved in the TGF-β signaling pathway, which facilitates the destruction of SnoN, a transcriptional co-suppressor, which leads in turn to the transactivation of TGF-β-responsive genes for cell cycle arrest. The function of APC was demonstrated in TGF-β signal transduction, but the mechanism by which it is activated in response to TGF-β signaling remains unclear. We report here that phosphorylation of Cdc27, a core subunit of APC, in response to TGF-β signaling can facilitate the activation of APC. We have demonstrated that casein kinase II (CKII) is involved in the phosphorylation of Cdc27 in response to TGF-β signaling. Depletion of CKII by shRNA abolishes the TGF-β-induced phosphorylation of Cdc27 and subsequent degradation of SnoN. Disruptive mutation of Cdc27 (S154A) attenuates TGF-β-induced SnoN degradation. In addition, expression of a phosphorylation-resistant Cdc27 mutant significantly attenuates TGF-β-induced growth inhibition. Together, the results suggest that phosphorylation of Cdc27 by CKII is involved in TGF-β-induced activation of APC.
authors.affiliation: Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Liyong
authors.initials: L
authors.lastname: Zhang
authors.forename: Takeo
authors.initials: T
authors.lastname: Fujita
authors.forename: George
authors.initials: G
authors.lastname: Wu
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Yong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D019943:Amino Acid Substitution; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008907:Mink; D020125:Mutation, Missense; D010766:Phosphorylation / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*
chemical_list: D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; C577366:CDC27 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; D016212:Transforming Growth Factor beta; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D047390:Casein Kinase II