Identification of an INSM1-binding site in the insulin promoter: negative regulation of the insulin gene transcription.

The Journal of Endocrinology
Hong-Wei WangMichael S Lan

Abstract

In this study, an insulinoma-associated antigen-1 (INSM1)-binding site in the proximal promoter sequence of the insulin gene was identified. The co-transfection of INSM1 with rat insulin I/II promoter-driven reporter genes exhibited a 40-50% inhibitory effect on the reporter activity. Mutational experiments were performed by introducing a substitution, GG to AT, into the INSM1 core binding site of the rat insulin I/II promoters. The mutated insulin promoter exhibited a three- to 20-fold increase in the promoter activity over the wild-type promoter in several insulinoma cell lines. Moreover, INSM1 overexpression exhibited no inhibitory effect on the mutated insulin promoter. Chromatin immunoprecipitation assays using beta TC-1, mouse fetal pancreas, and Ad-INSM1-transduced human islets demonstrated that INSM1 occupies the endogenous insulin promoter sequence containing the INSM1-binding site in vivo. The binding of the INSM1 to the insulin promoter could suppress approximately 50% of insulin message in human islets. The mechanism for transcriptional repression of the insulin gene by INSM1 is mediated through the recruitment of cyclin D1 and histone deacetylase-3 to the insulin promoter. Anti-INSM1 or anti-cyclin D1 morpholino tr...Continue Reading

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Citations

Jan 7, 2009·The Journal of Biological Chemistry·Tao ZhangMichael S Lan
Feb 28, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Michael S Lan, Mary B Breslin
Nov 11, 2009·PLoS Neglected Tropical Diseases·Marcela G DrummondGlória R Franco
Jun 12, 2013·Developmental Biology·Marie A Forbes-OsborneAnn C Morris
Sep 20, 2015·American Journal of Clinical Pathology·Jason N RosenbaumRicardo V Lloyd
Oct 12, 2018·Nature·Teerawat WiwatpanitJaime García-Añoveros
Nov 18, 2017·Journal of Cutaneous Pathology·Patrick S RushRicardo V Lloyd
May 23, 2019·Molecular Cancer Research : MCR·Chiachen ChenMichael S Lan

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