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Molecular and Cellular Biology, September 2003, p. 6000-6012, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.6000-6012.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Expression of MIS in the Testis Is Downregulated by Tumor Necrosis Factor Alpha through the Negative Regulation of SF-1 Transactivation by NF-B

Hormone Research Center,¹ Department of Biology, Chonnam National University, Gwangju 500-757,² Department of Pathology, School of Medicine, Chungnam National University, Daejeon 301-131,³ Center for Ligand and Transcription, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea⁴

Received 24 January 2003/ Returned for modification 21 March 2003/ Accepted 4 June 2003

The expression of Mullerian inhibiting substance (MIS), a key molecule in sex differentiation and reproduction, is tightly regulated. It has been suggested that meiotic germ cells repress MIS expression in testicular Sertoli cells, although the substance responsible for this cell-cell communication remains unknown. Here, we present the cytokine tumor necrosis factor alpha (TNF-) as a strong candidate for such a substance and its downstream molecular events. TNF- inhibited MIS expression in testis organ cultures, and TNF-^-/- testes showed high and prolonged MIS expression. Furthermore, in transient-transfection assays TNF- suppressed the MIS promoter that was activated by steroidogenic factor 1 (SF-1), one of the major transcription factors that regulate MIS expression. The modulation of SF-1 transactivation by TNF- is through the activation of NF-B, which subsequently interacts with SF-1 and represses its transactivation. The physical association of NF-B with SF-1 was shown by yeast two-hybrid protein interaction, glutathione S-transferase pull-down, and coimmunoprecipitation (ChIP) analyses. ChIP assays also revealed that endogenous NF-B, as well as SF-1, is recruited to the MIS promoter upon TNF- signaling. SF-1-bound NF-B subsequently recruits histone deacetylases to inhibit the SF-1-activated gene expression. These results may identify, for the first time, the responsible substance and its action mechanism underlying the repression of MIS expression by meiotic germ cells in the testis.

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