title: Mammalian target of rapamycin complex 1 signaling opposes the effects of anchorage loss, leading to activation of Cdk4 and Cdc6 stabilization.
abstract: When deprived of an anchorage to the extracellular matrix, fibroblasts arrest in the G(1) phase with inactivation of Cdk4/6 and Cdk2 and destruction of Cdc6, the assembler of prereplicative complexes essential for S phase onset. How cellular anchorages control these kinases and Cdc6 stability is poorly understood. Here, we report that in rat embryonic fibroblasts, activation of mammalian target of rapamycin complex 1 by a Tsc2 mutation or overexpression of a constitutively active mutant Rheb overrides the absence of the anchorage and stabilizes Cdc6 at least partly via activating Cdk4/6 that induces Emi1, an APC/C(Cdh1) ubiquitin ligase inhibitor.
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Arakawa-Takeuchi
authors.forename: Kohei
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Jung-ha
authors.initials: JH
authors.lastname: Park
authors.forename: Baasanjav
authors.initials: B
authors.lastname: Uranbileg
authors.forename: Hanako
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Shigeki
authors.initials: S
authors.lastname: Jinno
authors.forename: Hiroto
authors.initials: H
authors.lastname: Okayama
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D055550:Protein Stability; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: C528180:Cdc6 protein, rat; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C519510:Crtc1 protein, rat; C498962:Fbxo5 protein, rat; D014157:Transcription Factors; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D053148:Caspase 3