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¹ Oncology Institute, Cardinal Bernardin Cancer Center, and ² Pathology Department, Loyola University Medical Center, Maywood, IL 60153
³ Department of Biology, Loyola University Chicago, Chicago, IL 60626
⁴ Department of Host Defense and Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

CORRESPONDENCE J. Zhang: jzhang{at}lumc.edu

Transforming growth factor β–activated kinase 1 (TAK1), a member of the MAPKKK family, is a key mediator of proinflammatory and stress signals. Activation of TAK1 by proinflammatory cytokines and T and B cell receptors induces the nuclear localization of nuclear factor B (NF-B) and the activation of c-Jun N-terminal kinase (JNK)/AP1 and P38, which play important roles in mediating inflammation, immune responses, T and B cell activation, and epithelial cell survival. Here, we report that TAK1 is critical for the survival of both hematopoietic cells and hepatocytes. Deletion of TAK1 results in bone marrow (BM) and liver failure in mice due to the massive apoptotic death of hematopoietic cells and hepatocytes. Hematopoietic stem cells and progenitors were among those hematopoietic cells affected by TAK1 deletion–induced cell death. This apoptotic cell death is autonomous, as demonstrated by reciprocal BM transplantation. Deletion of TAK1 resulted in the inactivation of both JNK and NF-B signaling, as well as the down-regulation of expression of prosurvival genes.

M. Tang, X. Wei, and Y. Guo contributed equally to this paper.

X. Wei's present address is Henan Tumor Hospital, 127 Dongming Road, Zhengzhou 450008, China.

Y. Guo's present address is Dept. of Respiratory and Molecular Biology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.

© 2008 Tang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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