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Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBP alpha interaction

Fujimoto, T.; Anderson, Kristina LU ; Jacobsen, Sten Eirik W LU ; Nishikawa, S-i and Nerlov, C. (2007) In EMBO Journal 26(9). p.2361-2370
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 alpha or PU. 1. Cdk6 inhibits Runx1 activity by binding to the runt domain of Runx1, interfering with Runx1 DNA binding and Runx1-C/ EBPa 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.... (More)
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 alpha or PU. 1. Cdk6 inhibits Runx1 activity by binding to the runt domain of Runx1, interfering with Runx1 DNA binding and Runx1-C/ EBPa 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
hematopoiesis, cell cycle, c/EBP, cdk6, Runx1
in
EMBO Journal
volume
26
issue
9
pages
2361 - 2370
publisher
Oxford University Press
external identifiers
  • wos:000246187500013
  • scopus:34247571525
ISSN
1460-2075
DOI
10.1038/sj.emboj.7601675
language
English
LU publication?
yes
id
cebe20d6-67e0-4393-91e1-b2c985e4d9a1 (old id 662724)
date added to LUP
2007-12-07 11:37:14
date last changed
2017-06-25 04:27:55
@article{cebe20d6-67e0-4393-91e1-b2c985e4d9a1,
  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 alpha or PU. 1. Cdk6 inhibits Runx1 activity by binding to the runt domain of Runx1, interfering with Runx1 DNA binding and Runx1-C/ EBPa 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.},
  author       = {Fujimoto, T. and Anderson, Kristina and Jacobsen, Sten Eirik W and Nishikawa, S-i and Nerlov, C.},
  issn         = {1460-2075},
  keyword      = {hematopoiesis,cell cycle,c/EBP,cdk6,Runx1},
  language     = {eng},
  number       = {9},
  pages        = {2361--2370},
  publisher    = {Oxford University Press},
  series       = {EMBO Journal},
  title        = {Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBP alpha interaction},
  url          = {http://dx.doi.org/10.1038/sj.emboj.7601675},
  volume       = {26},
  year         = {2007},
}