The T-box factor Tpit recruits SRC/p160 co-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.
Maira
Mario
M
Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, Québec H2W 1R7, Canada.
Couture
Catherine
C
Le Martelot
Gwendal
G
Pulichino
Anne-Marie
AM
Bilodeau
Steve
S
Drouin
Jacques
J
D002460:Cell Line; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid / Q000378:metabolism / Q000502:physiology; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D006728:Hormones; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D020825:T-Box Domain Proteins; C486589:TBX19 protein, human; D014157:Transcription Factors; D011333:Pro-Opiomelanocortin; D003346:Corticotropin-Releasing Hormone; D017868:Cyclic AMP-Dependent Protein Kinases