Cdk1-mediated phosphorylation of human ATF7 at Thr-51 and Thr-53 promotes cell-cycle progression into M phase

Hitomi Hasegawa; Kenichi Ishibashi; Shoichi Kubota; Chihiro Yamaguchi; Ryuzaburo Yuki; Haruna Nakajo; Richard Eckner; Noritaka Yamaguchi; Kazunari K Yokoyama; Naoto Yamaguchi

doi:10.1371/journal.pone.0116048

Cdk1-mediated phosphorylation of human ATF7 at Thr-51 and Thr-53 promotes cell-cycle progression into M phase

PLoS One. 2014 Dec 29;9(12):e116048. doi: 10.1371/journal.pone.0116048. eCollection 2014.

Affiliations

¹ Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
² Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
³ Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Abstract

Activating transcription factor 2 (ATF2) and its homolog ATF7 are phosphorylated at Thr-69/Thr-71 and at Thr-51/Thr-53, respectively, by stress-activated MAPKs regulating their transcriptional functions in G1 and S phases. However, little is known about the role of ATF2 and ATF7 in G2/M phase. Here, we show that Cdk1-cyclin B1 phosphorylates ATF2 at Thr-69/Thr-71 and ATF7 at Thr-51/Thr-53 from early prophase to anaphase in the absence of any stress stimulation. Knockdown of ATF2 or ATF7 decreases the rate of cell proliferation and the number of cells in M-phase. In particular, the knockdown of ATF7 severely inhibits cell proliferation and G2/M progression. The inducible expression of a mitotically nonphosphorylatable version of ATF7 inhibits G2/M progression despite the presence of endogenous ATF7. We also show that mitotic phosphorylation of ATF7 promotes the activation of Aurora kinases, which are key enzymes for early mitotic events. These results suggest that the Cdk1-mediated phosphorylation of ATF7 facilitates G2/M progression, at least in part, by enabling Aurora signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 2 / chemistry
Activating Transcription Factor 2 / metabolism
Activating Transcription Factors / chemistry
Activating Transcription Factors / metabolism*
Amino Acid Sequence
Anaphase
Aurora Kinases / metabolism
CDC2 Protein Kinase / metabolism*
Cell Division*
G2 Phase
Gene Knockdown Techniques
HeLa Cells
Humans
Models, Biological
Molecular Sequence Data
Phosphorylation
Phosphothreonine / metabolism*
Prophase

Substances

ATF2 protein, human
ATF7 protein, human
Activating Transcription Factor 2
Activating Transcription Factors
Phosphothreonine
Aurora Kinases
CDC2 Protein Kinase

Grants and funding

This work was supported by Grants-in-aid for Scientific Research and the Global COE Program (G-COE, Global Center for Education and Research in Immune Regulation and Treatment) from the Japanese Ministry of Education, Culture, Sports, Science and Technology; Grants from Taiwan (NSC-101-2320-B-037-047-My3; NSC-101-2314-B-037-004-My2; NHRI-Ex102-10109BI; NHRI-102A1-PDCO-0310201; KMU-DT103001); G-COE Research Assistants (HH KI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.