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Transforming growth factor-β1 signaling represses testicular steroidogenesis through cross-talk with orphan nuclear

Eunsook Park1, Chin-Hee Song1, Jae-Il Park2

  • 1Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.

Plos One
|August 21, 2014
PubMed

Insights

Transforming growth factor-beta1 (TGF-β1) inhibits testicular steroidogenesis by repressing the orphan nuclear receptor Nur77. This TGF-β1/ALK5/Smad3 signaling pathway suppresses Nur77

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Reproductive Biology

Background:

  • Transforming growth factor-beta1 (TGF-β1) is known to inhibit luteinizing hormone (LH)-mediated steroidogenesis in testicular Leydig cells.
  • The precise molecular mechanisms underlying TGF-β1's control over Leydig cell steroidogenesis remain incompletely understood.

Purpose of the Study:

  • To investigate the role of cross-talk between TGF-β1 signaling and the orphan nuclear receptor Nur77 in regulating steroidogenesis in testicular Leydig cells.
  • To elucidate the molecular pathway through which TGF-β1 exerts its inhibitory effects on steroidogenic gene expression.

Main Methods:

  • Utilized mouse Leydig cells to assess the impact of TGF-β1 on testosterone production and steroidogenic gene expression (P450c17, StAR, 3β-HSD) in response to LH/cAMP stimulation.
  • Investigated the effect of TGF-β1/ALK5 signaling on promoter activity of steroidogenic genes activated by cAMP and Nur77.
  • Examined the interaction between TGF-β1/ALK5-activated Smad3 and Nur77 in regulating gene promoter binding.
  • Employed genetically modified mice (Tgfbr2flox/flox Cyp17iCre) to evaluate the in vivo relevance of the TGF-β1/Tgfbr2 pathway in Leydig cells.

Main Results:

  • TGF-β1 signaling significantly inhibited cAMP-induced testosterone production and the expression of key steroidogenic genes in mouse Leydig cells.
  • TGF-β1/ALK5 signaling repressed both cAMP-induced and Nur77-activated promoter activity of steroidogenic genes.
  • Smad3, activated by TGF-β1/ALK5, interfered with Nur77's DNA binding, thereby repressing Nur77's transactivation of steroidogenic gene promoters.
  • In Tgfbr2 conditional knockout mice, the inhibitory effect of TGF-β1 on steroidogenic gene expression was markedly reduced, confirming the pathway's importance.

Conclusions:

  • TGF-β1 signaling, via the ALK5/Smad3 pathway, represses testicular steroidogenesis by inhibiting Nur77's transactivation of steroidogenic genes in Leydig cells.
  • These findings reveal a novel molecular mechanism for TGF-β1-mediated repression of testicular steroidogenesis, highlighting the critical role of Nur77 regulation.

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