Premium
Contribution of MAP Kinases ERK1/2 in Beta Cell Function
Author(s) -
Dioum Elhadji Mamadou,
Schneider Jay W.,
Cobb Melanie H
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.659.5
Subject(s) - kinase , microbiology and biotechnology , transcription factor , mapk/erk pathway , signal transduction , beta cell , biology , mitogen activated protein kinase , islet , chemistry , gene , insulin , biochemistry , endocrinology
Pancreatic islet development and beta‐cell function are dependent on the coordinated activity of multiple islet‐enriched transcription factors, including PDX‐1, NKX6.1, MafA and BETA2. Somatic mutations in these factors have been implicated in maturity‐onset diabetes of the young (MODY). Understanding of the molecular mechanisms of pancreatic beta‐cell function and integrity is necessary for the development of anti‐diabetic drugs. Activation of the mitogen activated protein kinases (MAPKs) Extracellular signal‐related kinases 1 and 2 (ERK1/2) in beta cells is required for insulin gene transcription and secretion. Using in vitro and cell culture approaches, we showed that ERK1/2 phosphorylate BETA2, PDX‐1 and MafA and modulate their DNA binding activity and ability to form ternary complexes required for insulin gene transcription and beta‐cell function. Isoxazole, a compound identified in a small molecule screen, shows improved beta‐cell function through chromatin remodeling and transcription factor activation in a pleiotropic pathway involving ERK1/2. We are exploring the molecular mechanisms involved in this signal transduction pathway. Source of funding: NIH R37 DK34128 NIH RO1 DIC55310