Transcriptional and translational regulation of β-cell differentiation factor Nkx6.1

Hirotaka Watada, Raghavendra G. Mirmira, Joey Leung, Michael S. German

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

In the mature pancreas, the homeodomain transcription factor Nkx6.1 is uniquely restricted to β-cells. Nkx6.1 also is expressed in developing β-cells and plays an essential role in their differentiation. Among cell lines, both β- and α-cell lines express nkx6.1 mRNA; but no protein can be detected in the α-cell lines, suggesting that post-transcriptional regulation contributes to the restriction of Nkx6.1 to β-cells. To investigate the regulator of Nkx6.1 expression, we outlined the structure of the mouse nkx6.1 gene, and we identified regions that direct cell type-specific expression. The nkx6.1 gene has a long 5'-untranslated region (5'-UTR) downstream of a cluster of transcription start sites. nkx6.1 gene sequences from -5.6 to +1.0 kilobase pairs have specific promoter activity in β-cell lines but not in NIH3T3 cells. This activity is dependent on sequences located at about -800 base pairs and on the 5'-UTR. Electrophoretic mobility shift assays demonstrate that homeodomain transcription factors PDX1 and Nkx2.2 can bind to the sequence element located at -800 base pairs. In addition, dicistronic assays establish that the 5'-UTR region functions as a potent internal ribosomal entry site, providing cell type-specific regulation of translation. These data demonstrate that complex regulation of both Nkx6.1 transcription and translation provides the specificity of expression required during pancreas development.

Original languageEnglish (US)
Pages (from-to)34224-34230
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number44
DOIs
StatePublished - Nov 3 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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