Salt-inducible kinase regulates corticotropin releasing hormone transcription in hypothalamic neurons by controlling the activity of the CREB co-activator, TORC

Wednesday, October 26, 2011 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center	NICHD	ENDOC-8

Authors

• Y Liu
• V Poon
• G Sanchez-Watts
• AG Watts
• G Aguilera

Abstract

Interaction of the CREB co-activator, transducer of regulated CREB activity (TORC) with the CRH promoter is essential for initiating CRH transcription. In basal conditions, Ser/Thr protein kinases of the AMP-dependent protein kinases (AMPK) family, including salt-inducible kinase (SIK) maintain TORC in the cytoplasm by phosphorylation. In situ hybridization studies showed low basal levels of AMPK, SIK1 and SIK2 mRNA in the dorsomedial hypothalamic paraventricular nucleus (PVN) of rats, but only SIK1 mRNA increased markedly after 1h restraint stress. SIK1 was inducible by the adenylate cyclase, forskolin, in hypothalamic neurons in vitro. However, overexpression of either SIK1 or SIK2 in 4B cells reduced nuclear TORC2 levels (western blot) and inhibited forskolin-stimulated CRH transcription. Conversely, the non-selective SIK inhibitor, staurosporine, increased nuclear TORC2 content and stimulated CRH transcription in 4Bcells, and primary neuronal cultures (heteronuclear RNA). Unexpectedly, in 4B cells specific shRNA knock down of endogenous SIK2 but not SIK1 induced nuclear translocation of TORC2 and CRH transcription, suggesting that SIK2 mediates TORC inactivation in basal conditions, while induction of SIK1 limits transcriptional activation. The study provides evidence that SIK represses CRH transcription by inactivating TORC, serving as a mechanism for rapid on/off control of CRH transcription.

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