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PMID: 18689679 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Synergistic control of T cell development and tumor suppression by diacylglycerol kinase alpha and zeta.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 33 ·2008-08-19 ·Pages 11909-14

Guo R, Wan CK, Carpenter JH, Mousallem T, Boustany RM, Kuan CT, Burks AW, Zhong XP

Abstract

Diacylglycerol (DAG) kinases (DGKs) are a family of enzymes that convert DAG to phosphatidic acid (PA), the physiologic functions of which have been poorly defined. We report here that DGK alpha and zeta synergistically promote T cell maturation in the thymus. Absence of both DGKalpha and zeta (DGKalpha(-/-)zeta(-/-)) results in a severe decrease in the number of CD4(+)CD8(-) and CD4(-)CD8(+) single-positive thymocytes correlating with increased DAG-mediated signaling. Positive selection, but not negative selection, is impaired in DGKalpha(-/-)zeta(-/-) mice. The developmental blockage in DGKalpha(-/-)zeta(-/-) mice can be partially overcome by treatment with PA. Furthermore, decreased DGK activity also promotes thymic lymphomagenesis accompanying elevated Ras and Erk1/2 activation. Our data demonstrate a synergistic and critical role of DGK isoforms in T cell development and tumor suppression, and indicate that DGKs not only terminate DAG signaling but also initiate PA signaling in thymocytes to promote positive selection.

MeSH Terms
Animals Cell Differentiation/immunology Cell Transformation, Neoplastic/genetics,immunology,metabolism,pathology Diacylglycerol Kinase/deficiency,genetics,metabolism Enzyme Activation Female Isoenzymes/metabolism Lymphoma/enzymology,genetics,immunology,pathology Male Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinase 1/metabolism Mitogen-Activated Protein Kinase 3/metabolism T-Lymphocytes/cytology,immunology Thymus Gland/enzymology Tissue Culture Techniques ras Proteins/metabolism
Chemicals
Isoenzymes Diacylglycerol Kinase Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 ras Proteins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Guo Rishu
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Wan Chi-Keung
Carpenter Jeffery H
Mousallem Talal
Boustany Rose-Mary N
Kuan Chien-Tsun
Burks A Wesley
Zhong Xiao-Ping
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0711856105
Published
2008-08-19
Epub
2008-00-08
Pages
11909-14
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2575297
Subset
IM
Grants
NIAID NIH HHS · R01 AI076357 · United States
External Links
PubMed source DOI: 10.1073/pnas.0711856105 PMC Full Text View journal details
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