The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation.

The cloning of genes encoding mammalian DNA binding transcription factors for RNA polymerase II has provided the opportunity to analyze the structure and function of these proteins. This review summarizes recent studies that define structural domains for DNA binding and transcriptional activation functions in sequence-specific transcription factors. The mechanisms by which these factors may activate transcriptional initiation and by which they may be regulated to achieve differential gene expression are also discussed.

https://science.sciencemag.org/content/sci/245/4916/371.full.pdf

Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins

https://www.cell.com/cell/pdf/0092-8674(92)90154-5.pdf

Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member

Signaling--2000 and beyond.

Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133

A nuclear protein, CREB, has been isolated from rat brain and shown to stimulate transcription of the cyclic AMP-responsive gene somatostatin as a dimer. Biochemical analysis suggests that dimerization and transcriptional efficacy of CREB protein in vitro are regulated by phosphorylation. These findings demonstrate that cellular signals can modulate gene expression by regulating the covalent modification of pre-existing nuclear factors.

Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB.

Cyclic AMP regulates the expression of a number of genes through a conserved promoter element, the CRE1. Moreover, transcrip-tional induction by cAMP requires the activation of cAMP-dependent protein kinase (protein kinase A)1,2. We have previously characterized the cAMP response element binding protein (CREB) in PC 12 cells and brain tissue as a nuclear factor, of relative molecular mass 43,000, whose transcriptional efficacy is regulated by protein kinase A phosphorylation3,4. CREB stimulates transcription on binding to the CRE as a dimer. Experiments suggesting that the dimerization and transcriptional efficacy of CREB are each stimulated by phosphorylation at distinct sites prompted us to suggest that CREB is regulated by multiple kinases in vivo4. We now report the isolation of a cDNA clone for rat CREB using amino-acid sequence information from purified CREB protein. Sequence analysis of this CREB cDNA predicts a cluster of protein kinase A, protein kinase C and casein kinase II consensus recognition sites near the N terminus of the protein. The proximity of these potential phosphorylation sites to one another indicates that they may interact either positively or negatively to regulate CREB bioactivity.

A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence

Regulation of cAMP-inducible genes by CREB.

Cyclic AMP mediates the hormonal stimulation of a number of eukaryotic genes by directing the protein kinase A (PK-A)-dependent phosphorylation of transcription factor CREB. We have previously determined that although phosphorylation at Ser-133 is critical for induction, this site does not appear to participate directly in transactivation. To test the hypothesis that CREB ultimately activates transcription through domains that are distinct from the PK-A site, we constructed a series of CREB mutants and evaluated them by transient assays in F9 teratocarcinoma cells. Remarkably, a glutamine-rich region near the N terminus appeared to be important for PK-A-mediated induction of CREB since removal of this domain caused a marked reduction in CREB activity. A second region consisting of a short acidic motif (DLSSD) C terminal to the PK-A site also appeared to synergize with the phosphorylation motif to permit transcriptional activation. Biochemical experiments with purified recombinant CREB protein further demonstrate that the transactivation domain is more sensitive to trypsin digestion than are the DNA-binding and dimerization domains, suggesting that the activator region may be structured to permit interactions with other proteins in the RNA polymerase II complex.

Gustavo A. Gonzalez

Papers

Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133

Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB.

A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence

Regulation of cAMP-inducible genes by CREB.

Characterization of motifs which are critical for activity of the cyclic AMP-responsive transcription factor CREB.