Involvement of GSK-3β and DYRK1B in differentiation-inducing factor-3-induced phosphorylation of cyclin D1 in HeLa cells

Fumi Takahashi-Yanaga, Jun Mori, Etsuko Matsuzaki, Yutaka Watanabe, Masato Hirata, Yoshikazu Miwa, Sachio Morimoto, Toshiyuki Sasaguri

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40 Citations (Scopus)

Abstract

Differentiation-inducing factors (DIFs) are putative morphogens that induce cell differentiation in Dictyostelium discoideum. We previously reported that DIF-3 activates glycogen synthase kinase-3β (GSK-3β), resulting in the degradation of cyclin D1 in HeLa cells. In this study, we investigated the effect of DIF-3 on cyclin D1 mutants (R29Q, L32A, T286A, T288A, and T286A/T288A) to clarify the precise mechanisms by which DIF-3 degrades cyclin D1 in HeLa cells. We revealed that T286A, T288A, and T286A/T288A mutants were resistant to DIF-3-induced degradation compared with wild-type cyclin D1, indicating that the phosphorylation of Thr286 and Thr288 were critical for cyclin D1 degradation induced by DIF-3. Indeed, DIF-3 markedly elevated the phosphorylation level of cyclin D1, and mutations introduced to Thr 286 and/or Thr288 prevented the phosphorylation induced by DIF-3. Depletion of endogenous GSK-3β and dual-specificity tyrosine phosphorylation regulated kinase 1B (DYRK1B) by RNA interference attenuated the DIF-3-induced cyclin D1 phosphorylation and degradation. The effect of DIF-3 on DYRK1B activity was examined and we found that DIF-3 also activated this kinase. Further, we found that not only GSK-3β but also DYRK1B modulates cyclin D1 subcellular localization by the phosphorylation of Thr288. These results suggest that DIF-3 induces degradation of cyclin D1 through the GSK-3β- and DYRK1B-mediated threonine phosphorylation in HeLa cells.

Original languageEnglish
Pages (from-to)38489-38497
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number50
DOIs
Publication statusPublished - Dec 15 2006

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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