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Science 22 October 1999:
Vol. 286. no. 5440, pp. 790 - 793
DOI: 10.1126/science.286.5440.790
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Reports

Apoptosis of T Cells Mediated by Ca2+-Induced Release of the Transcription Factor MEF2

Hong-Duk Youn, 1 Luo Sun, 1 Ron Prywes, 4 Jun O. Liu 123*

T cell receptor (TCR)-induced apoptosis of thymocytes is mediated by calcium-dependent expression of the steroid receptors Nur77 and Nor1. Nur77 expression is controlled by the transcription factor myocyte enhancer factor 2 (MEF2), but how MEF2 is activated by calcium signaling is still obscure. Cabin1, a calcineurin inhibitor, was found to regulate MEF2. MEF2 was normally sequestered by Cabin1 in a transcriptionally inactive state. TCR engagement led to an increase in intracellular calcium concentration and the dissociation of MEF2 from Cabin1, as a result of competitive binding of activated calmodulin to Cabin1. The interplay between Cabin1, MEF2, and calmodulin defines a distinct signaling pathway from the TCR to the Nur77 promoter during T cell apoptosis.

1 Center for Cancer Research,
2 Department of Biology,
3 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4 Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
*   To whom correspondence should be addressed. E-mail: Junliu{at}mit.edu

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 275, 8719-8725
   Abstract »    Full Text »    PDF »
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H.-D. Youn, C. M. Grozinger, and J. O. Liu (2000)
J. Biol. Chem. 275, 22563-22567
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J. Biol. Chem. 275, 34017-34020
   Abstract »    Full Text »    PDF »
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W. Zhu, I. Shiojima, Y. Hiroi, Y. Zou, H. Akazawa, M. Mizukami, H. Toko, Y. Yazaki, R. Nagai, and I. Komuro (2000)
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