Article
- The EMBO Journal (2007) 26, 2361 - 2370
- doi:10.1038/sj.emboj.7601675
Published online: 12 April 2007
Subject Categories:
Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBP
interaction
T Fujimoto1,4, K Anderson2, SEW Jacobsen2, S-i Nishikawa3 and C Nerlov1
- EMBL Mouse Biology Unit, Monterotondo, Italy
- Department of Stem Cell Biology, Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden
- RIKEN, Center for Developmental Biology, Minatoshima-minami-machi, Kobe, Japan
- Division of Cell Differentiation, IMEG, Kumamoto University, Kumamoto, Japan
Correspondence to:
C Nerlov, EMBL Mouse Biology Unit, Via Ramarini 32, 00016 Monterotondo 16, Italy. Tel: +39 06 9009 1218; Fax: +39 06 9009 1272; E-mail: nerlov@embl-monterotondo.it
Received 20 November 2006; Accepted 8 March 2007
Abstract
Interactions between the cell cycle machinery and transcription factors play a central role in coordinating terminal differentiation and proliferation arrest. We here show that cyclin-dependent kinase 6 (Cdk6) is specifically expressed in proliferating hematopoietic progenitor cells, and that Cdk6 inhibits transcriptional activation by Runx1, but not C/EBP
or PU.1. Cdk6 inhibits Runx1 activity by binding to the runt domain of Runx1, interfering with Runx1 DNA binding and Runx1-C/EBP interaction. Cdk6 expression increased myeloid progenitor proliferation, and inhibited myeloid lineage-specific gene expression and terminal differentiation in vitro and in vivo. These effects of Cdk6 did not require Cdk6 kinase activity. Cdk6-mediated inhibition of granulocytic differentiation could be reversed by excess Runx1, consistent with Runx1 being the major target for Cdk6. We propose that Cdk6 downregulation in myeloid progenitors releases Runx1 from Cdk6 inhibition, thereby allowing terminal differentiation. Since Runx transcription factors play central roles in hematopoietic, neuronal and osteogenic lineages, this novel, noncanonical Cdk6 function may control terminal differentiation in multiple tissues and cell types.
Keywords:
- C/EBP,
- cdk6,
- cell cycle,
- hematopoiesis,
- Runx1
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