Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells

  1. Wolfgang Breitwieser1,
  2. Steve Lyons1,
  3. Ann Marie Flenniken1,5,
  4. Garry Ashton2,
  5. Gail Bruder1,
  6. Mark Willington1,
  7. Georges Lacaud3,
  8. Valerie Kouskoff4, and
  9. Nic Jones1,6
  1. 1 Cell Regulation Department, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom;
  2. 2 Histology Department, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom;
  3. 3 Stem Cell Biology Department, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom;
  4. 4 Stem Cell and Haematopoiesis Department, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom

Abstract

The ATF2 transcription factor is phosphorylated by the stress-activated mitogen-activated protein kinases (MAPKs) JNK and p38. We show that this phosphorylation is essential for ATF2 function in vivo, since a mouse carrying mutations in the critical phosphorylation sites has a strong phenotype identical to that seen upon deletion of the DNA-binding domain. In addition, combining this mutant with a knockout of the ATF2 homolog, ATF7, results in embryonic lethality with severe abnormalities in the developing liver and heart. The mutant fetal liver is characterized by high levels of apoptosis in developing hepatocytes and haematopoietic cells. Furthermore, we observe a significant increase in active p38 due to loss of a negative feedback loop involving the ATF2-dependent transcriptional activation of MAPK phosphatases. In embryonic liver cells, this increase drives apoptosis, since it can be suppressed by chemical inhibition of p38. Our findings demonstrate the importance of finely regulating the activities of MAPKs during development.

Keywords

Footnotes

  • 5 Present address: Centre for Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.

  • 6 Corresponding author.

    6 E-MAIL njones{at}picr.man.ac.uk; FAX 44-161-4463038.

  • Supplemental material is available at http://www.genesdev.org.

  • Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.430207

    • Received February 22, 2007.
    • Accepted June 28, 2007.
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