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J. Biol. Chem., Vol. 278, Issue 29, 26695-26703, July 18, 2003

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Nuclear Factor of Activated T Cells 2 Transactivation in Mast Cells

A NOVEL ISOFORM-SPECIFIC TRANSACTIVATION DOMAIN CONFERS UNIQUE FcRI RESPONSIVENESS^*

M. Benjamin Hock  and Melissa A. Brown   ¶

From the Department of Pathology and Graduate Program in Genetics and Molecular Biology, Emory University School of Medicine, Atlanta, Georgia 30322

Murine nuclear factor of activated T cells (NFAT)2./ differ by 42 and 28 unique amino-terminal amino acids and are differentially expressed. Both isoforms share conserved domains that regulate DNA-binding and subcellular localization. A genetic "one-hybrid" assay was used to define two distinct transactivation (TA) domains: in addition to a conserved TAD present in both isoforms, a second, novel TAD exists within the -specific amino terminus. Pharmacologic inhibitors Gö6976 and rottlerin demonstrate that both conventional and novel protein kinase C (PKC) family members regulate endogenous mast cell NFAT activity, and NFAT2 TA. Overexpression of dominant active PKC (which has been implicated in immune receptor signaling) induces NFAT2./ TA. Mutations within the smallest PKC-responsive transactivation domain demonstrate that the PKC effect is at least partially indirect. Significantly, the -specific domain confers greater ability to TA in response to treatment with phorbol 12-myristate 13-acetate/ionomycin or lipopolysaccharide, and unique sensitivity to FcRI signaling. Accordingly, overexpression of NFAT2. results in significantly greater NFAT- and interleukin-4 reporter activity than NFAT2.. These results suggest that whereas NFAT2 isoforms may share redundant DNA-binding preferences, there are specialized functional consequences of their isoform-specific domains.

Received for publication, January 30, 2003 , and in revised form, May 7, 2003.

^* This work was supported by National Institutes of Health Grant CA047992 (to M. A. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Northwestern University School of Medicine, Dept. of Microbiology and Immunology, Tarry Medical Research Bldg., Rm. 7-711, mail code S213, 320 East Superior St., Chicago, IL 60611-3010. Tel.: 312-503-0108; Fax: 312-503-1339; E-mail: m-brown12{at}northwestern.edu.

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