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Molecular and Cellular Biology, September 2008, p. 5777-5784, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00106-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Diadenosine Tetraphosphate Hydrolase Is Part of the Transcriptional Regulation Network in Immunologically Activated Mast Cells{triangledown}

Irit Carmi-Levy,1 Nurit Yannay-Cohen,1 Gillian Kay,1 Ehud Razin,1* and Hovav Nechushtan2

Department of Biochemistry, Hebrew University Hadassah Medical School, P.O. Box 12272, Jerusalem 91120, Israel,1 Oncology Department, Hadassah Hebrew University Medical Center, P.O. Box 12272, Jerusalem 91120, Israel2

Received 20 January 2008/ Returned for modification 27 February 2008/ Accepted 7 July 2008

We previously discovered that microphthalmia transcription factor (MITF) and upstream stimulatory factor 2 (USF2) each forms a complex with its inhibitor histidine triad nucleotide-binding 1 (Hint-1) and with lysyl-tRNA synthetase (LysRS). Moreover, we showed that the dinucleotide diadenosine tetraphosphate (Ap4A), previously shown to be synthesized by LysRS, binds to Hint-1, and as a result the transcription factors are released from their suppression. Thus, transcriptional activity is regulated by Ap4A, suggesting that Ap4A is a second messenger in this context. For Ap4A to be unambiguously established as a second messenger, several criteria have to be fulfilled, including the presence of a metabolizing enzyme. Since several enzymes are able to hydrolize Ap4A, we provided here evidence that the "Nudix" type 2 gene product, Ap4A hydrolase, is responsible for Ap4A degradation following the immunological activation of mast cells. The knockdown of Ap4A hydrolase modulated Ap4A accumulation, resulting in changes in the expression of MITF and USF2 target genes. Moreover, our observations demonstrated that the involvement of Ap4A hydrolase in gene regulation is not a phenomenon exclusive to mast cells but can also be found in cardiac cells activated with the β-agonist isoproterenol. Thus, we have provided concrete evidence establishing Ap4A as a second messenger in the regulation of gene expression.

* Corresponding author. Mailing address: Department of Biochemistry, Hebrew University Hadassah Medical School, P.O. Box 12272, Jerusalem 91120, Israel. Phone: 972 2 675 8288. Fax: 972 2 675 7379. E-mail: ehudr{at}ekmd.huji.ac.il

{triangledown} Published ahead of print on 21 July 2008.

Molecular and Cellular Biology, September 2008, p. 5777-5784, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00106-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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