The T-box Factor Tpit Recruits SRC/p160 Co-activators and Mediates Hormone Action

Abstract

Tpit (Tbx19) is a transcription factor belonging to the T-box family, and it is essential for late differentiation of pituitary pro-opiomelanocortin (POMC)-expressing corticotroph and melanotroph cells. Tpit is also required, both in humans and mice, for cell-specific expression of the POMC gene in cooperation with the homeoprotein Pitx1. Despite their important roles as developmental regulators, the molecular mechanisms underpinning the functions of T-box factors in general, and of Tpit in particular, are still poorly defined. We now report that Tpit functions as an activator of transcription by recruiting SRC/p160 co-activators to its cognate DNA target in the POMC promoter, the Tpit/Pitx-RE. We also show that Tpit is a mediator of hormone signaling and that the Tpit/Pitx-RE is responsive to signals elicited by hypothalamic corticotropin-releasing hormone. These signals are mediated by the cAMP-dependent protein kinase and mitogen-activated protein kinase pathways, and activation of cAMP-dependent protein kinase also enhances Tpit and SRC-dependent transcription. We have previously shown that corticotropin-releasing hormone action is also exerted at the POMC promoter through the orphan nuclear receptor NGFI-B and its recruitment of SRC co-activators. Given that Tpit exhibits transcriptional synergy with NGFI-B, our results suggest that Tpit, along with NGFI-B and SRC-2, is part of a transcription regulatory complex assembled on the POMC promoter in response to hormonal stimulation.

Corticotropin-releasing hormone or dexamethasone regulates rat proopiomelanocortin transcription through Tpit/Pitx-responsive element in its promoter

“…These results suggest that Tpit/PitxRE as well as NurRE have responsiveness to CRH/cAMP treatment consistent with previous reports (Kovalovsky et al 2002, Maira et al 2003b.…”

“…In addition to ACTH secretion, the calcium influx also induces the activation of POMC mRNA transcription (von Dreden et al 1988) and POMC promoter activity (Kovalovsky et al 2002). Activation of the PKA pathway also induces ERK1/2 (MAPK) cascade activation on POMCgene expression (Kovalovsky et al 2002, Maira et al 2003b.…”

“…Activated Nur factors bind to the target DNA element in the POMC promoter, Nur-responsive element (NurRE), as a homo-or hetero-dimer (Maira et al 1999(Maira et al , 2003a. CRHinduced NurRE-dependent POMC transcription is mediated via PKA/CAM-KII/ERK1/2 cascades in AtT-20 cells (Kovalovsky et al 2002, Maira et al 2003b.…”

“…In addition to Nur factors, Tpit mediates CRH-induced activation of POMC transcription, which involves the activation of cAMP and ERK1/2 signals (Maira et al 2003b). Tpit recruits steroid receptor co-activator (SRC)/p160 co-activators in response to CRH stimulation, cooperating with Nur77, resulting in the assembly of a complex of transcription factors and co-activators on the POMC promoter, enhancing POMC transcription.…”

Nur77 gene expression levels were involved in different ACTH-secretion autonomy between Cushing’s disease and subclinical Cushing’s disease

“…Tpit is exclusively expressed in pituitary POMC-expressing lineages, and is essential for cellspecific transcription of the POMC gene [16]. Maria et al reported that Tpit and Nur77 cooperatively induce POMC gene expression [17]. The present study showed that there was no significant difference in POMC mRNA levels between subCD and CD.…”