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Context-dependent regulation of NeuroD activity and protein accumulation
Context-dependent regulation of NeuroD activity and protein accumulation.
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NeuroD/BETA2 (referred to as NeuroD hereafter) is a basic helix-loop-helix (bHLH) transcription factor that is required for the development and survival of a subset of neurons and pancreatic endocrine cells in mice. Gain-of-function analyses demonstrated that NeuroD can (i) convert epidermal fate into neuronal fate when overexpressed in Xenopus embryos, and (ii) activate the insulin promoter in pancreatic beta cell lines in response to glucose stimulation. In glucose-stimulated INS-1 pancreatic beta cells, mutations of S259, S266, and S274 to alanines inhibited the ability of NeuroD to activate the insulin promoter. Phosphorylation of those serine residues by ERK1/2 was required for NeuroD activity in that assay. To determine whether the same residues are implicated in the neurogenic activity of NeuroD, we mutated the conserved S259, S266, and S274 of Xenopus NeuroD to alanines (S259A, S266A, and S274A), and performed an ectopic neurogenesis assay in Xenopus embryos. In contrast to what has been observed in the pancreatic beta cell line, the S266A and S274A mutant forms of Xenopus NeuroD displayed significantly increased abilities to form ectopic neurons, while S259A had little effect. In addition, S266A and S274A of Xenopus NeuroD resulted in increased accumulation of protein in the injected embryos while the corresponding mutations on mouse NeuroD did not have the same effect in an insulinoma cell line. Our results demonstrate that the consequence of NeuroD protein modification is context-dependent at both the molecular and functional levels.
Dufton C, Marcora E, Chae JH, McCullough J, Eby J, Hausburg M, Stein GH, Khoo S, Cobb MH, Lee JE
Molecular and cellular neurosciences
2005-04-01 00:00
28
4
727-36
Amino Acid Sequence,Amino Acid Substitution,Animals,Basic Helix-Loop-Helix Transcription Factors,Cell Line, Tumor,Cricetinae,Female,Mice,Molecular Sequence Data,Nerve Tissue Proteins,Neurons,Phosphorylation,Serine,Xenopus Proteins,Xenopus laevis,Basic Helix-Loop-Helix Transcription Factors,Nerve Tissue Proteins,Xenopus Proteins,NeuroD protein,Serine
Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Campus Box 347, Boulder, CO 80309-0347, USA
Mol. Cell. Neurosci.
NIDDK R01 DK55310, NINDS R01 NS35118, NIGMS T32 GM07135, NIDDK U19 DK061248
1044-7431
10.1016/j.mcn.2004.12.004
S1044-7431(04)00297-0
1081
True
15797719
