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.
Highlights
The activating transcription factors (ATFs) belong to the AP-1 family of transcription factors [1]
To examine whether Activating transcription factor 2 (ATF2) and ATF7 are involved in cell-cycle progression into G2/M phases, we chose the following knockdown target sequences: the first sequence was common among the human ATF2 variants, and the other two sequences were the sequences in the coding sequence (CDS) and the 39-untranslated region (39UTR) of human ATF7
ATF7 knockdown strongly affected the level of the ATF2 protein (Fig. 1B, S1B-E Fig.), none of the ATF2 transcript variants contain any detectable homology to the shATF7(39UTR) and shATF7(CDS) sequences
Summary
The activating transcription factors (ATFs) belong to the AP-1 family of transcription factors [1]. ATF2 and ATF7 (originally called ATFa) have highly homologous sequences [2,3,4] and are ubiquitously expressed in various tissues [5, 6]. Knockout mutations of PLOS ONE | DOI:10.1371/journal.pone.0116048. Mitotic Phosphorylation of ATF7 by Cdk1-Cyclin B1. ATF2 and ATF7 lead to early postnatal lethality and abnormal behavioral traits reminiscent of isolation-reared wild-type mice, respectively [7, 8]. The ATF2 and ATF7 double knockout mice die during embryogenesis with abnormalities in the developing liver and heart [2]
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