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Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1‐C/EBPα interaction
Author(s) -
Fujimoto T,
Anderson K,
Jacobsen SEW,
Nishikawa Si,
Nerlov C
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601675
Subject(s) - stem cell , stem cell biology , runx1 , biology , haematopoiesis , genetics , embryo , reproductive technology , embryogenesis
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/EBPα or PU.1. Cdk6 inhibits Runx1 activity by binding to the runt domain of Runx1, interfering with Runx1 DNA binding and Runx1‐C/EBPα 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.