Involvement of CREB-regulated transcription coactivators (CRTC) in transcriptional activation of steroidogenic acute regulatory protein (Star) by ACTH

Lorna I. F. Smith, Victoria Huang, Mark Olah, Loc Trinh, Ying Liu, Georgina Hazell, Becky Conway-Campbell, Zidong Zhao, Antoine Martinez, Anne-Marie Lefrancois-Martinez, Stafford Lightman, Francesca Spiga, Greti Aguilera

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Abstract

Studies in vivo have suggested the involvement of CREB-regulated transcription coactivator (CRTC)2 on ACTHinduced transcription of the key steroidogenic protein, Steroidogenic Acute Regulatory (StAR). The present study uses two ACTH-responsive adrenocortical cell lines, to examine the role of CRTC on Star transcription. Here we show that ACTH-induced Star primary transcript, or heteronuclear RNA (hnRNA), parallels rapid increases in nuclear levels of the 3 isoforms of CRTC; CRTC1, CRTC2 and CRTC3. Furthermore, ACTH promotes recruitment of CRTC2 and CRTC3 by the Star promoter and siRNA knockdown of either CRTC3 or CRTC2 attenuates the increases in ACTH-induced Star hnRNA. Using pharmacological inhibitors of PKA, MAP kinase and calcineurin, we show that the effects of ACTH on Star transcription and CRTC nuclear translocation depend predominantly on the PKA pathway. The data provides evidence that CRTC2 and CRTC3, contribute to activation of Star transcription by ACTH, and that PKA/CRTC-dependent pathways are part of the multifactorial mechanisms regulating Star transcription.
Original languageEnglish
Article number110612
Number of pages11
JournalMolecular and Cellular Endocrinology
Volume499
Early online date8 Oct 2019
DOIs
Publication statusPublished - 1 Jan 2020

Keywords

  • CRTC
  • StAR
  • CREB
  • Steroidogenesis
  • Adrenal cortex
  • Transcription

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