Nkx2.2 Activates the Ghrelin Promoter in Pancreatic Islet Cells

被引:15
作者
Hill, Jonathon T. [1 ]
Chao, Christina S. [2 ]
Anderson, Keith R. [2 ]
Kaufman, Fernanda [2 ]
Johnson, Christopher W. [2 ]
Sussel, Lori [1 ]
机构
[1] Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA
[2] Univ Colorado Denver, Dept Biochem & Mol Genet, Aurora, CO 80045 USA
基金
美国国家卫生研究院;
关键词
FOOD-INTAKE; IN-VIVO; INSULIN-SECRETION; ACYLATED PEPTIDE; EPSILON-CELLS; RAT PANCREAS; BETA-CELLS; EXPRESSION; ENDOCRINE; MOUSE;
D O I
10.1210/me.2009-0360
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Nkx2.2 is an essential regulator of pancreatic endocrine differentiation. Nkx2.2-null mice are completely devoid of beta-ells and have a large reduction of alpha- and PP cells. In the place of these islet populations, there is a corresponding increase in the ghrelin-positive epsilon-cells. Molecular studies have indicated that Nkx2.2 functions as an activator and repressor to regulate islet cell fate decisions. To determine whether Nkx2.2 is solely important for islet cell fate decisions or also has the capability to control ghrelin at the promoter level, we studied the transcriptional regulation of the ghrelin promoter within the pancreas, in vitro and in vivo. These studies demonstrate that both of the previously identified transcriptional start sites in the ghrelin promoter are active within the embryonic pancreas; however, the long transcript is preferentially up-regulated in the Nkx2.2-null pancreas. We also show that the promoter region between -619 and -488 bp upstream of the translational start site is necessary for repression of ghrelin in alpha TC1 and beta TC6 cells. Surprisingly, we also show that Nkx2.2 is able to bind to and activate the ghrelin promoter in several cell lines that do or do not express endogenous ghrelin. Together, these results suggest that the up-regulation of ghrelin expression in the Nkx2.2-null mice is not due to loss of repression of the ghrelin promoter in the nonghrelin islet populations. Furthermore, Nkx2.2 may contribute to the activation of ghrelin in mature islet epsilon-cells. ( Molecular Endocrinology 24: 381-390, 2010)
引用
收藏
页码:381 / 390
页数:10
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