scholarly journals The Islet β Cell-enriched MafA Activator Is a Key Regulator of Insulin Gene Transcription

2005 ◽  
Vol 280 (12) ◽  
pp. 11887-11894 ◽  
Author(s):  
Li Zhao ◽  
Min Guo ◽  
Taka-aki Matsuoka ◽  
Derek K. Hagman ◽  
Susan D. Parazzoli ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Insulin Gene ◽  
Β Cell ◽  
Insulin Gene Transcription

scholarly journals PIASy is a SUMOylation-independent negative regulator of the insulin transactivator MafA

2019 ◽  
Vol 63 (4) ◽  
pp. 297-308
Author(s):  
Suzuka Onishi ◽  
Kohsuke Kataoka
Keyword(s):  
Transcription Factors ◽  
Gene Transcription ◽  
Gene Promoter ◽  
Terminal Region ◽  
Insulin Gene ◽  
Negative Regulator ◽  
Β Cell ◽  
E3 Ligases ◽  
Amino Terminal ◽  
Insulin Gene Transcription

Insulin plays a central role in glucose homeostasis and is produced exclusively by pancreatic islet β-cells. Insulin gene transcription is regulated by a set of β-cell-enriched transcription factors that bind to cis-regulatory elements within the promoter region, and regulation of the insulin gene promoter is closely linked to β-cell functionality. PIASy, a member of the PIAS family of SUMO E3 ligases, is thought to affect insulin gene transcription, but its mechanism of action is not fully understood. Here, we demonstrate that PIASy interacts with MafA and represses insulin gene promoter activity. MafA is a β-cell-restricted basic leucine-zipper transcriptional activator that binds to the C1 element of the insulin gene promoter. In line with previous studies showing the transactivator domain of MafA is SUMOylated, PIASy enhanced the SUMOylation of MafA. However, a SUMOylation-deficient mutant of MafA was still repressed by PIASy, indicating that this modification is dispensable for repression. Using a series of MafA and PIASy mutants, we found that the basic domain of MafA and the amino-terminal region of PIASy containing the SAP domain are necessary for their interaction. In addition, SUMO-interacting motif 1 (SIM1) at the carboxyl-terminal region of PIASy was required to repress the synergistic transactivation of MafA, Pdx1, and Beta2, transcription factors playing central roles in β-cell differentiation and function. The PINIT and SP-RING domains in the middle region of PIASy were dispensable. These findings suggest that PIASy binds to MafA through the SAP domain and negatively regulates the insulin gene promoter through a novel SIM1-dependent mechanism.

scholarly journals Insulin Gene Transcription Is Mediated by Interactions between the p300 Coactivator and PDX-1, BETA2, and E47

2002 ◽  
Vol 22 (2) ◽  
pp. 412-420 ◽  
Author(s):  
Yi Qiu ◽  
Min Guo ◽  
Suming Huang ◽  
Roland Stein
Keyword(s):  
Dna Binding ◽  
Rna Polymerase Ii ◽  
Gene Transcription ◽  
Present Report ◽  
Amino Acid Sequences ◽  
Insulin Gene ◽  
Homeodomain Protein ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Gene Transcription

ABSTRACT Pancreatic β-cell-type-specific expression of the insulin gene requires both ubiquitous and cell-enriched activators, which are organized within the enhancer region into a network of protein-protein and protein-DNA interactions to promote transcriptional synergy. Protein-protein-mediated communication between DNA-bound activators and the RNA polymerase II transcriptional machinery is inhibited by the adenovirus E1A protein as a result of E1A’s binding to the p300 coactivator. E1A disrupts signaling between the non-DNA-binding p300 protein and the basic helix-loop-helix DNA-binding factors of insulin’s E-element activator (i.e., the islet-enriched BETA2 and generally distributed E47 proteins), as well as a distinct but unidentified enhancer factor. In the present report, we show that E1A binding to p300 prevents activation by insulin’s β-cell-enriched PDX-1 activator. p300 interacts directly with the N-terminal region of the PDX-1 homeodomain protein, which contains conserved amino acid sequences essential for activation. The unique combination of PDX-1, BETA2, E47, and p300 was shown to promote synergistic activation from a transfected insulin enhancer-driven reporter construct in non-β cells, a process inhibited by E1A. In addition, E1A inhibited the level of PDX-1 and BETA2 complex formation in β cells. These results indicate that E1A inhibits insulin gene transcription by preventing communication between the p300 coactivator and key DNA-bound activators, like PDX-1 and BETA2:E47.

scholarly journals SOCS-1 Protein Prevents Janus Kinase/STAT-dependent Inhibition of β Cell Insulin Gene Transcription and Secretion in Response to Interferon-γ

2001 ◽  
Vol 276 (28) ◽  
pp. 25862-25870 ◽  
Author(s):  
Sandra Cottet ◽  
Philippe Dupraz ◽  
Fabienne Hamburger ◽  
Wanda Dolci ◽  
Muriel Jaquet ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Interferon Γ ◽  
Insulin Gene ◽  
Janus Kinase ◽  
Β Cell ◽  
Dependent Inhibition ◽  
Insulin Gene Transcription

scholarly journals Analysis of the Role of E2A-Encoded Proteins in Insulin Gene Transcription

1997 ◽  
Vol 11 (11) ◽  
pp. 1608-1617 ◽  
Author(s):  
Arun Sharma ◽  
Eva Henderson ◽  
Laura Gamer ◽  
Yuan Zhuang ◽  
Roland Stein
Keyword(s):  
Gene Transcription ◽  
Present Report ◽  
Insulin Gene ◽  
Apparent Difference ◽  
Transactivation Domain ◽  
Β Cell ◽  
Helix Loop Helix ◽  
Encoded Proteins ◽  
Gene Enhancer ◽  
Insulin Gene Transcription

Abstract Pancreatic β-cell type-specific transcription of the insulin gene is mediated, in part, by factors in the basic helix-loop-helix (bHLH) family that act on a site within the insulin enhancer, termed the E1-box. Expression from this element is regulated by a heteromeric protein complex containing ubiquitous (i.e. the E2A- and HEB-encoded proteins) and islet-enriched members of the bHLH family. Recent studies indicate that the E2A- and HEB-encoded proteins contain a transactivation domain, termed AD2, that functions more efficiently in transfected β-cell lines. In the present report, we extend this observation by demonstrating that expression of full-length E2A proteins (E47, E12, and E2/5) activates insulin E element-directed transcription in a β-cell line-selective manner. Stimulation required functional interactions with other key insulin gene transcription factors, including its islet bHLH partner as well as those that act on the RIPE3b1 and RIPE3a2 elements of the insulin gene enhancer. The conserved AD2 domain in the E2A proteins was essential in this process. The effect of the E2A- and HEB-encoded proteins on insulin gene expression was also analyzed in mice lacking a functional E2A or HEB gene. There was no apparent difference in insulin production between wild type, heterozygote, and homozygous mutant E2A or HEB mice. These results suggest that neither the E2A- or HEB-encoded proteins are essential for insulin transcription and that one factor can substitute for the other to impart normal insulin E1 activator function in mutant animals.

Analysis of ∼700 Human Tissue Samples Identifies microRNAs That Are Associated with, Predictive of, and Necessary for Insulin Gene Transcription

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 2160-P
Author(s):  
ANAND HARDIKAR ◽  
WILSON WONG ◽  
MUGDHA JOGLEKAR ◽  
LOUISE T. DALGAARD ◽  
ALICIA JENKINS ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Human Tissue ◽  
Insulin Gene ◽  
Tissue Samples ◽  
Insulin Gene Transcription

scholarly journals Glucose Regulation of Insulin Gene Transcription and Pre-mRNA Processing in Human Islets

Diabetes ◽  
2007 ◽  
Vol 56 (3) ◽  
pp. 827-835 ◽  
Author(s):  
C. Evans-Molina ◽  
J. C. Garmey ◽  
R. Ketchum ◽  
K. L. Brayman ◽  
S. Deng ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Human Islets ◽  
Mrna Processing ◽  
Insulin Gene ◽  
Glucose Regulation ◽  
Insulin Gene Transcription
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