Abstract

Transcription factor (RIPE3b1) binding to the insulin gene enhancer element RIPE3b (A2-C1) is selectively expressed in pancreatic beta cells, and plays an important role in regulating beta cell specific expression of the insulin gene. In addition, the RIPE3b1 factor is a major glucose responsive transcriptional regulator of beta-cell function. Transcription factors BETA2 and PDX-1 are also important for regulating beta cell specific and glucose responsive expression of the insulin gene. Additionally, PDX-1 and BETA2, play a major role in pancreatic development and differentiation of beta cells. Hence, we hypothesize that the RIPE3b1 factor will be a major regulator of pancreatic beta cell function and pancreatic development. Using a combination of biochemical purification, amino acid sequence determination, we have successfully identified and cloned the RIPE3b1 factor as a novel mammalian homologue of the avian MafA/L-Maf factor (mMafA). Avian homologue of RIPE3b1 is an important differentiation factor that is 1) highly restricted in its expression, 2) can induce expression of several genes, and 3) when expressed ectopically induce differentiation. This is consistent with our hypothesis for a role of RIPE3b1 factor in regulating function, development and differentiation of pancreatic beta cells. Furthermore, we show that the RIPE3b1 gene is expressed only in pancreatic beta cells and not in alpha cells, supporting role of this factor in differentiation of beta cells. Hence, we propose to perform targeted ablation of the gene in mice to determine the role of the RIPE3b1 activator in pancreatic development. When expressed as a transgene, we will determine the ability of this factor to induce insulin gene expression in non-insulin producing cells, and to characterize the mechanisms by which the RIPE3b1 activator regulates insulin expression. Results from these studies will be instrumental in developing new strategies for beta cell replacement as a treatment for diabetes. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060127-03
Application #
6845973
Study Section
Endocrinology Study Section (END)
Program Officer
Sato, Sheryl M
Project Start
2003-03-01
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
3
Fiscal Year
2005
Total Cost
$336,000
Indirect Cost

  Institution

Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

El Khattabi, Ilham; Sharma, Arun (2015) Proper activation of MafA is required for optimal differentiation and maturation of pancreatic ?-cells. Best Pract Res Clin Endocrinol Metab 29:821-31
Nishimura, Wataru; Kapoor, Archana; El Khattabi, Ilham et al. (2015) Compensatory Response by Late Embryonic Tubular Epithelium to the Reduction in Pancreatic Progenitors. PLoS One 10:e0142286
Nomoto, Hiroshi; Kondo, Takuma; Miyoshi, Hideaki et al. (2015) Inhibition of Small Maf Function in Pancreatic ?-Cells Improves Glucose Tolerance Through the Enhancement of Insulin Gene Transcription and Insulin Secretion. Endocrinology 156:3570-80
He, KaiHui Hu; Juhl, Kirstine; Karadimos, Michael et al. (2014) Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA. Dev Biol 385:2-12
El Khattabi, Ilham; Sharma, Arun (2013) Preventing p38 MAPK-mediated MafA degradation ameliorates ?-cell dysfunction under oxidative stress. Mol Endocrinol 27:1078-90
Aguayo-Mazzucato, Cristina; Zavacki, Ann Marie; Marinelarena, Alejandra et al. (2013) Thyroid hormone promotes postnatal rat pancreatic ýý-cell development and glucose-responsive insulin secretion through MAFA. Diabetes 62:1569-80
Karadimos, Michael J; Kapoor, Archana; El Khattabi, Ilham et al. (2012) ýý-cell preservation and regeneration for diabetes treatment: where are we now? Diabetes Manag (Lond) 2:213-222
Aguayo-Mazzucato, C; Koh, A; El Khattabi, I et al. (2011) Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells. Diabetologia 54:583-93
Juhl, Kirstine; Bonner-Weir, Susan; Sharma, Arun (2010) Regenerating pancreatic beta-cells: plasticity of adult pancreatic cells and the feasibility of in-vivo neogenesis. Curr Opin Organ Transplant 15:79-85
Kondo, Takuma; El Khattabi, Ilham; Nishimura, Wataru et al. (2009) p38 MAPK is a major regulator of MafA protein stability under oxidative stress. Mol Endocrinol 23:1281-90

Showing the most recent 10 out of 16 publications