Mammalian target of rapamycin complex 1 signaling opposes the effects of anchorage loss, leading to activation of Cdk4 and Cdc6 stabilization.
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.
Arakawa-Takeuchi
Shiho
S
Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Kobayashi
Kohei
K
Park
Jung-ha
JH
Uranbileg
Baasanjav
B
Yamamoto
Hanako
H
Jinno
Shigeki
S
Okayama
Hiroto
H
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
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