Expression of MIS in the testis is downregulated by tumor necrosis factor alpha through the negative regulation of SF-1 transactivation by NF-κB

Cheol Yi Hong, Jin Hee Park, Kook Heon Seo, Jin Man Kim, Suhn Young Im, Jae Lee, Hueng Sik Choi, Keesook Lee

Research output: Contribution to journalArticle

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Abstract

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-α) as a strong candidate for such a substance and its downstream molecular events. TNF-α inhibited MIS expression in testis organ cultures, and TNF-α-/- testes showed high and prolonged MIS expression. Furthermore, in transient-transfection assays TNF-α 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-α is through the activation of NF-κB, which subsequently interacts with SF-1 and represses its transactivation. The physical association of NF-κB 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-κB, as well as SF-1, is recruited to the MIS promoter upon TNF-α signaling. SF-1-bound NF-κB 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.

Original languageEnglish (US)
Pages (from-to)6000-6012
Number of pages13
JournalMolecular and Cellular Biology
Volume23
Issue number17
DOIs
StatePublished - Sep 2003
Externally publishedYes

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Steroidogenic Factor 1
Anti-Mullerian Hormone
Transcriptional Activation
Testis
Down-Regulation
Tumor Necrosis Factor-alpha
Germ Cells
Sex Differentiation
Histone Deacetylases
Sertoli Cells
Organ Culture Techniques
Glutathione Transferase
Cell Communication
Reproduction
Transfection
Transcription Factors
Yeasts
Cytokines
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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Expression of MIS in the testis is downregulated by tumor necrosis factor alpha through the negative regulation of SF-1 transactivation by NF-κB. / Hong, Cheol Yi; Park, Jin Hee; Seo, Kook Heon; Kim, Jin Man; Im, Suhn Young; Lee, Jae; Choi, Hueng Sik; Lee, Keesook.

In: Molecular and Cellular Biology, Vol. 23, No. 17, 09.2003, p. 6000-6012.

Research output: Contribution to journalArticle

Hong, Cheol Yi ; Park, Jin Hee ; Seo, Kook Heon ; Kim, Jin Man ; Im, Suhn Young ; Lee, Jae ; Choi, Hueng Sik ; Lee, Keesook. / Expression of MIS in the testis is downregulated by tumor necrosis factor alpha through the negative regulation of SF-1 transactivation by NF-κB. In: Molecular and Cellular Biology. 2003 ; Vol. 23, No. 17. pp. 6000-6012.
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