TY - JOUR
T1 - Differential regulation of CHOP-10/GADD153 gene expression by MAPK signaling in pancreatic β-cells
AU - Lawrence, Michael C.
AU - McGlynn, Kathleen
AU - Naziruddin, Bashoo
AU - Levy, Marlon F.
AU - Cobb, Melanie H.
PY - 2007/7/10
Y1 - 2007/7/10
N2 - CHOP-10 (GADD153/DDIT-3) is a bZIP protein involved in differentiation and apoptosis. Its expression is induced in response to stresses such as nutrient deprivation, perturbation of the endoplasmic reticulum, redox imbalance, and UV exposure. Here we show that CHOP expression is induced in cultured pancreatic β-cells maintained in a basal glucose concentration of 5.5 mM and repressed by stimulatory glucose (≥11 mM). Both induction and repression of CHOP are dependent on the MAPKs ERK1 and ERK2. Two regulatory composite sites containing overlapping MafA response elements (MARE) and CAAT enhancer binding (CEB) elements regulate transcription in an ERK1/2-dependent manner. One site (MARE-CEB), from -320 to -300 bp in the promoter, represses transcription. The other site (CEB-MARE), from +2,628 to +2,641 bp in the first intron of the CHOP gene, activates it. MafA can influence transcription of both sites. The MARE-CEB is repressed by MafA, whereas the CEB-MARE site, which is homologous to the A2C1 component of the glucose-sensitive RIPE3b region of the insulin gene promoter, is activated by MafA. These results indicate that ERK1/2 have dual roles in regulating CHOP gene expression via both promoter and intronic regions, depending on environmental and metabolic stresses imposed on pancreatic β-cells.
AB - CHOP-10 (GADD153/DDIT-3) is a bZIP protein involved in differentiation and apoptosis. Its expression is induced in response to stresses such as nutrient deprivation, perturbation of the endoplasmic reticulum, redox imbalance, and UV exposure. Here we show that CHOP expression is induced in cultured pancreatic β-cells maintained in a basal glucose concentration of 5.5 mM and repressed by stimulatory glucose (≥11 mM). Both induction and repression of CHOP are dependent on the MAPKs ERK1 and ERK2. Two regulatory composite sites containing overlapping MafA response elements (MARE) and CAAT enhancer binding (CEB) elements regulate transcription in an ERK1/2-dependent manner. One site (MARE-CEB), from -320 to -300 bp in the promoter, represses transcription. The other site (CEB-MARE), from +2,628 to +2,641 bp in the first intron of the CHOP gene, activates it. MafA can influence transcription of both sites. The MARE-CEB is repressed by MafA, whereas the CEB-MARE site, which is homologous to the A2C1 component of the glucose-sensitive RIPE3b region of the insulin gene promoter, is activated by MafA. These results indicate that ERK1/2 have dual roles in regulating CHOP gene expression via both promoter and intronic regions, depending on environmental and metabolic stresses imposed on pancreatic β-cells.
KW - Cellular stress
KW - Extracellular signal-regulated kinase
KW - Intron
KW - MafA
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U2 - 10.1073/pnas.0704618104
DO - 10.1073/pnas.0704618104
M3 - Article
C2 - 17615236
AN - SCOPUS:34547419547
SN - 0027-8424
VL - 104
SP - 11518
EP - 11525
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 28
ER -