POU homeodomain protein Oct-1 functions as a sensor for cyclic AMP.
Cyclic AMP is a fundamentally important second messenger for numerous peptide hormones and neurotransmitters that control gene expression, cell proliferation, and metabolic homeostasis. Here we show that cAMP works with the POU homeodomain protein Oct-1 to regulate gene expression in pancreatic and intestinal endocrine cells. This ubiquitously expressed transcription factor is known as a stress sensor. We found that it also functions as a repressor of Cdx-2, a proglucagon gene activator. Through a mechanism that involves the activation of exchange protein activated by cyclic AMP, elevation of cAMP leads to enhanced phosphorylation and nuclear exclusion of Oct-1 and reduced interactions between Oct-1 or nuclear co-repressors and the Cdx-2 gene promoter, detected by chromatin immunoprecipitation. In rat primary pancreatic islet cells, cAMP elevation also reduces nuclear Oct-1 content, which causes increased proglucagon and proinsulin mRNA expression. Our study therefore identifies a novel mechanism by which cAMP regulates hormone-gene expression and suggests that ubiquitously expressed Oct-1 may play a role in metabolic homeostasis by functioning as a sensor for cAMP.
Wang
Peixiang
P
Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada.
Wang
Qinghua
Q
Sun
Jane
J
Wu
Jing
J
Li
Hang
H
Zhang
Nina
N
Huang
Yachi
Y
Su
Brenda
B
Li
Ren-ke
RK
Liu
Ling
L
Zhang
Yi
Y
Elsholtz
Harry P
HP
Hu
Jim
J
Gaisano
Herbert Y
HY
Jin
Tianru
T
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D002460:Cell Line; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; C539127:NCOR1 protein, human; C539129:Ncor1 protein, rat; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D050811:Octamer Transcription Factor-1; D012097:Repressor Proteins; D015534:Trans-Activators; D005576:Colforsin; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine