Pit-1β reduces transcription and CREB-binding protein recruitment in a DNA context-dependent manner

Abstract

Many transcription factors are expressed as multiple isoforms with distinct effects on the regulation of gene expression, and the functional consequences of structural differences between transcription factor isoforms may allow for precise control of gene expression. The pituitary transcription factor isoforms Pit-1 and Pit-1 differentially regulate anterior pituitary hormone gene expression. Pit-1 is required for the development of and appropriate hormone expression by anterior pituitary somatotrophs and lactotrophs. Pit-1 differs structurally from Pit-1 by the splice-insertion of the 26-residue -domain in the transactivation domain, and it differs functionally from Pit-1 in that it represses expression of the prolactin promoter in a cell-type specific manner. In order to identify signal and promoter context requirements for repression by Pit-1 , we examined its function in the presence of physiological regulatory signals as well as wild-type and mutant Pit-1-dependent target promoters. Here, we demonstrate that Pit-1 impairs recruitment of cAMP response elementbinding protein (CREB)-binding protein to the promoters that it represses. In addition, we show that repression of target promoter activity, reduction in promoter histone acetylation, and decrease of CREB-binding protein recruitment all depend on promoter context. These findings provide a mechanism for promoter-specific repression by Pit-1 .

Identification of a novel mutation in the exon 2 splice donor site of the POU1F1/PIT‐1 gene in Japanese identical twins with mild combined pituitary hormone deficiency

“…6-Luc and rGH0.6-Luc constructs were significantly elevated, reflecting endogenous gene expressions. Consistent with previous observations showing that cotransfection with wild-type POU1F1 elicited only marginal enhancements of target promoter activities in pituitary cells, 11,21 the introduction of POU1F1-WT into GH3 cells showed only small but significant increases in reporter gene activities, with maximum inductions of 1AE22-and 1AE17-fold for Prl and Gh promoters, respectively. Unlike with POU1F1-WT, transfection of POU1F1-D48-72 significantly suppressed rGH0.6-Luc activity in a dose-dependent manner (53AE9% inhibition at the max-imum dose), while suppressing rPRL0.6-Luc activity only at the highest dose (84AE5% inhibition).…”

Critical Role of the HMGA2 Gene in Pituitary Adenomas

“…Interestingly, several data indicate the ability of PIT-1 to recruit CBP/p300 which promotes the histones acetylation. 27 This would suggest that the induction of an increased histone acetylase activity with following acetylation of E2F1 may also contribute to the pathogenesis of pituitary adenomas. However, even though other genes might have also a role in the process of tumorigenesis, it appears clear that, in the absence of E2F1 protein, the pituitary cells are not able to progress to a clear neoplastic phenotype, and that likely other mechanisms, such as those above described, may converge on the E2F1 pathway.…”

Histone Acetylation Patterns of Typical and Atypical Pituitary Adenomas Indicate Epigenetic Shift of these Tumours

“…However, the mechanisms involved in this process are still unknown. Although there are a large number of studies on methylation patterns of pituitary tumours (7,(11)(12)(13), studies on histone acetylation patterns of these tumours are still limited (28)(29)(30).…”