title: Transduced p16INK4a peptides inhibit hypophosphorylation of the retinoblastoma protein and cell cycle progression prior to activation of Cdk2 complexes in late G1.
abstract: Progression of cells through the G1 phase of the cell cycle requires cyclin D:Cdk4/6 and cyclin E:Cdk2 complexes; however, the duration and ordering of these complexes remain unclear. To address this, we synthesized a peptidyl mimetic of the Cdk4/6 inhibitor, p16INK4a that contained an NH2-terminal TAT protein transduction domain. Transduction of TAT-p16 wild-type peptides into cells resulted in the loss of active, hypophosphorylated pRb and elicited an early G1 cell cycle arrest, provided cyclin E:Cdk2 complexes were inactive. We conclude that cyclin D:Cdk4/6 activity is required for early G1 phase cell cycle progression up to, but not beyond, activation of cyclin E:Cdk2 complexes at the restriction point and is thus nonredundant with cyclin E:Cdk2 in late G1.
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Gius
authors.forename: S A
authors.initials: SA
authors.lastname: Ezhevsky
authors.forename: M
authors.initials: M
authors.lastname: Becker-Hapak
authors.forename: H
authors.initials: H
authors.lastname: Nagahara
authors.forename: M C
authors.initials: MC
authors.lastname: Wei
authors.forename: S F
authors.initials: SF
authors.lastname: Dowdy
mesh_terms: D042846:CDC2-CDC28 Kinases; D002460:Cell Line; D056741:Cyclin D; D019927:Cyclin E / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D016213:Cyclins / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014162:Transfection
chemical_list: D056741:Cyclin D; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases