The T-box factor Tpit recruits SRC/p 160Co-activators and mediates hormone action

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.