LIN-9 phosphorylation on threonine-96 is required for transcriptional activation of LIN-9 target genes and promotes cell cycle progression.
Cell cycle transitions are governed by the timely expression of cyclins, the activating subunits of Cyclin-dependent kinases (Cdks), which are responsible for the inactivation of the pocket proteins. Overexpression of cyclins promotes cell proliferation and cancer. Therefore, it is important to understand the mechanisms by which cyclins regulate the expression of cell cycle promoting genes including subsequent cyclins. LIN-9 and the pocket proteins p107 and p130 are members of the DREAM complex that in G0 represses cell cycle genes. Interestingly, little is know about the regulation and function of LIN-9 after phosphorylation of p107,p130 by Cyclin D/Cdk4 disassembles the DREAM complex in early G1. In this report, we demonstrate that cyclin E1/Cdk3 phosphorylates LIN-9 on Thr-96. Mutating Thr-96 to alanine inhibits activation of cyclins A2 and B1 promoters, whereas a phosphomimetic Asp mutant strongly activates their promoters and triggers accelerated entry into G2/M phase in 293T cells. Taken together, our data suggest a novel role for cyclin E1 beyond G1/S and into S/G2 phase, most likely by inducing the expression of subsequent cyclins A2 and B1 through LIN-9.
Department of Pharmacology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America.
Frank
F
Eckerdt
Department of Pharmacology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America.
Mathew
M
Perez-Neut
Department of Pharmacology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America.
Oscar R
OR
Colamonici
D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D050720:Retinoblastoma-Like Protein p107 / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; C501563:LIN9 protein, human; D009687:Nuclear Proteins; C493844:RBL1 protein, human; D050720:Retinoblastoma-Like Protein p107; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D013912:Threonine