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Sequential actions of ERK1/2 on the AP‐1 transcription factor allow temporal integration of metabolic signals in pancreatic β cells
Author(s) -
Glauser Dominique A.,
Schlegel Werner
Publication year - 2007
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/fj.06-7798com
Subject(s) - transcription factor , transcription (linguistics) , microbiology and biotechnology , biology , stimulation , c fos , gene expression , protein subunit , chemistry , gene , biochemistry , endocrinology , philosophy , linguistics
The AP‐1 transcription factor composed of fos and jun gene products mediates transcriptional responses to hormonal and metabolic stimulations of pancreatic beta cells. Here, we investigated the mechanisms that dynamically control expression of AP‐1 subunit proteins. In MIN6 cells, glucose and GLP‐1 raised c‐FOS protein with biphasic kinetics, an initial peak being followed by a plateau that persisted as long as stimuli were maintained. ERK1/2 activation paralleled c‐FOS expression. Whereas initial induction of c‐FOS protein required ERK1/2‐dependent activation of c‐fos transcription and de novo protein synthesis, persistent accumulation of c‐FOS under sustained stimulation did not. Indeed, dependent on ERK1/2 activation, c‐FOS accumulated in its hyperphosphorylated form protected from degradation through the protea‐some pathway. The implication of ERK1/2 in the accumulation of c‐FOS protein was confirmed in rat primary β cells, and the functional consequences of this mechanism were demonstrated with DNA‐binding and reporter assays. Altogether these findings reveal a sequential regulation of AP‐1 by ERK1/2, which initially increases transcription of c ‐fos and, if stimulation persists, stabilizes freshly synthesized c‐FOS protein to efficiently activate the transcription of AP‐1‐regulated genes. This ERK1/2‐AP‐1 module can function as a temporal integrator converting metabolic stimuli of different durations into differential transcriptional outputs.—Glauser, D. A., Schlegel, W. Sequential actions of ERK1/2 on the AP‐1 transcription factor allow temporal integration of metabolic signals in pancreatic β cells. FASEB J. 21, 3240–3249 (2007)