期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 46, 页码 38438-38444出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M508594200
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资金
- NCI NIH HHS [5T32 CA09385-18, CA68485] Funding Source: Medline
- NIDDK NIH HHS [R01 DK-50203, DK20593, P60 DK20593] Funding Source: Medline
PDX-1 regulates transcription of genes involved in islet beta cell function and pancreas development. Islet-specific expression is controlled by 5'-flanking sequences from base pair (bp) - 2917 to - 1918 in transgenic experiments, which encompasses both conserved (i.e. Area I (bp - 2761/ - 2457), Area II (bp - 2153/ - 1923)) and non-conserved pdx-1 sequences. However, only an Area II-driven transgene is independently active in vivo, albeit in only a fraction of islet PDX-1-producing cells. Our objective was to identify the sequences within the - 2917/ - 1918-bp region that act in conjunction with Area II to allow comprehensive expression in islet PDX-1(+) cells. In cell line-based transfection assays, only Area I effectively potentiated Area II activity. Both Area I and Area II functioned in an orientation-independent manner, whereas synergistic, enhancer-like activation was uniquely found with duplicated Area II. Chimeras of Area II and the generally active SV40 enhancer or the beta cell-specific insulin enhancer suggested that islet cell-enriched activators were necessary for Area I activation, because Area II-mediated stimulation was reduced by the SV40 enhancer and activated by the insulin enhancer. Several conserved sites within Area I were important in Area I/Area II activation, with binding at bp - 2614/ - 2609 specifically controlled by Nkx2.2, an insulin gene regulator that is required for terminal beta cell differentiation. The ability of Area I to modulate Area II activation was also observed in vivo, as an Area I/Area II-driven transgene recapitulated the endogenous pdx-1 expression pattern in developing and adult islet cells. These results suggest that Area II is a central pdx-1 control region, whose islet cell activity is uniquely modified by Area I regulatory factors.
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