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Gene interactions and pathways from curated databases and text-mining
Mol Cell Biol 2008, PMID: 18086876

Glucose-dependent insulinotropic polypeptide-mediated up-regulation of beta-cell antiapoptotic Bcl-2 gene expression is coordinated by cyclic AMP (cAMP) response element binding protein (CREB) and cAMP-responsive CREB coactivator 2.

Kim, Su-Jin; Nian, Cuilan; Widenmaier, Scott; McIntosh, Christopher H S

The cyclic AMP (cAMP)/protein kinase A (PKA) cascade plays a central role in beta-cell proliferation and apoptosis. Here, we show that the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates expression of the antiapoptotic Bcl-2 gene in pancreatic beta cells through a pathway involving AMP-activated protein kinase (AMPK), cAMP-responsive CREB coactivator 2 (TORC2), and cAMP response element binding protein (CREB). Stimulation of beta-INS-1 (clone 832/13) cells with GIP resulted in increased Bcl-2 promoter activity. Analysis of the rat Bcl-2 promoter revealed two potential cAMP response elements, one of which (CRE-I [GTGACGTAC]) was shown, using mutagenesis and deletion analysis, to be functional. Subsequent studies established that GIP increased the nuclear localization of TORC2 and phosphorylation of CREB serine 133 through a pathway involving PKA activation and reduced AMPK phosphorylation. At the nuclear level, phospho-CREB and TORC2 were demonstrated to bind to CRE-I of the Bcl-2 promoter, and GIP treatment resulted in increases in their interaction. Furthermore, GIP-mediated cytoprotection was partially reversed by small interfering RNA-mediated reduction in BCL-2 or TORC2/CREB or by pharmacological activation of AMPK. The antiapoptotic effect of GIP in beta cells is therefore partially mediated through a novel mode of transcriptional regulation of Bcl-2 involving cAMP/PKA/AMPK-dependent regulation of CREB/TORC2 activity.

Document information provided by NCBI PubMed

Text Mining Data

Bcl-2 ⊣ GIP: " Stimulation of beta-INS-1 ( clone 832/13 ) cells with GIP resulted in increased Bcl-2 promoter activity "

TORC2 → GIP: " Subsequent studies established that GIP increased the nuclear localization of TORC2 and phosphorylation of CREB serine 133 through a pathway involving PKA activation and reduced AMPK phosphorylation "

CREB/TORC2 → cAMP/PKA/AMPK: " The antiapoptotic effect of GIP in beta cells is therefore partially mediated through a novel mode of transcriptional regulation of Bcl-2 involving cAMP/PKA/AMPK dependent regulation of CREB/TORC2 activity "

CREB/TORC2 → cAMP/PKA/AMPK: " The antiapoptotic effect of GIP in beta cells is therefore partially mediated through a novel mode of transcriptional regulation of Bcl-2 involving cAMP/PKA/AMPK dependent regulation of CREB/TORC2 activity "

CREB/TORC2 → cAMP/PKA/AMPK: " The antiapoptotic effect of GIP in beta cells is therefore partially mediated through a novel mode of transcriptional regulation of Bcl-2 involving cAMP/PKA/AMPK dependent regulation of CREB/TORC2 activity "

CREB/TORC2 → cAMP/PKA/AMPK: " The antiapoptotic effect of GIP in beta cells is therefore partially mediated through a novel mode of transcriptional regulation of Bcl-2 involving cAMP/PKA/AMPK dependent regulation of CREB/TORC2 activity "

Manually curated Databases

No curated data.