TORCs

Self Cite

883

862

Hormones and nutrients often induce genetic programs via signaling pathways that interface with gene-specific activators. Activation of the cAMP pathway, for example, stimulates cellular gene expression by means of the PKA-mediated phosphorylation of cAMP-response element binding protein (CREB) at Ser-133. Here, we use genome-wide approaches to characterize target genes that are regulated by CREB in different cellular contexts. CREB was found to occupy Ϸ4,000 promoter sites in vivo, depending on the presence and methylation state of consensus cAMP response elements near the promoter. The profiles for CREB occupancy were very similar in different human tissues, and exposure to a cAMP agonist stimulated CREB phosphorylation over a majority of these sites. Only a small proportion of CREB target genes was induced by cAMP in any cell type, however, due in part to the preferential recruitment of the coactivator CREB-binding protein to those promoters. These results indicate that CREB phosphorylation alone is not a reliable predictor of target gene activation and that additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter.cAMP ͉ cAMP-response element binding protein-binding protein ͉ DNA methylation T he concept of a transcription code that dictates gene expression by means of the concerted action of multiple promoter elements has served as a useful paradigm for understanding specificity in gene regulation. The ability of multiple transcription factors to recruit RNA polymerase II to the promoter by means of low affinity interactions with components of the transcriptional machinery has been documented extensively (1).By contrast with this model, other studies suggest that some activators per se are sufficient to mediate transcriptional responses to hormonal signals depending on the occupancy of relevant sites (1). Indeed, genome-wide studies comparing binding patterns of hepatic nuclear factors in the liver and endocrine pancreas indicate that selective occupancy may often explain how different genetic programs are activated in distinct cell types (2).The cAMP-response element binding protein (CREB) family of activators stimulates cellular gene expression after phosphorylation at a conserved serine (Ser-133 in CREB1) in response to cAMP (3). Ser-133 phosphorylation promotes target gene activation in part by means of recruitment of the coactivator paralogs CREB-binding protein (CBP)͞p300 (4). Recruitment of CBP by phospho-CREB (P-CREB) appears sufficient for induction of cellular genes in response to cAMP (5, 6); in vitro transcription studies indicate that P-CREB is capable of promoting assembly of the transcriptional apparatus independent of other regulatory inputs (7).By contrast, some reports suggest that other upstream activators in addition to CREB are required for cellular gene induction by cAMP (8). Indeed, the notion that CREB coordinates with other transcription factors is supported by recent animal studies in which CREB appeared to elicit the expressi...

Section: Discussionmentioning

confidence: 57%

Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues

Zhang

Odom

Koo

et al. 2005

Self Cite

883

862

“…The characterization of CREB-TORC interaction has shown that TORCs bind to the CREB bZIP DNA-binding domain in an arginine 314-dependent manner (1,3). We thus transfected cortical neurons with CREB constructs either lacking the bZIP domain or with an Arg314Ala mutation, and compared their activity to the wild-type CREB constructs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…T ransducers of regulated cAMP-response element-binding protein (CREB) activity (TORCs) are newly discovered coactivators that dramatically increase CREB's transcriptional activity independently of CREB Ser-133 phosphorylation (1,2). Recently, it has been shown that TORC2 functions as a pancreatic coincidence detector.…”

mentioning

confidence: 99%

TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity

Kovács

Steullet

Steinmann

et al. 2007

168

199

A key feature of memory processes is to link different input signals by association and to preserve this coupling at the level of synaptic connections. Late-phase long-term potentiation (L-LTP), a form of synaptic plasticity thought to encode long-term memory, requires gene transcription and protein synthesis. In this study, we report that a recently cloned coactivator of cAMP-response elementbinding protein (CREB), called transducer of regulated CREB activity 1 (TORC1), contributes to this process by sensing the coincidence of calcium and cAMP signals in neurons and by converting it into a transcriptional response that leads to the synthesis of factors required for enhanced synaptic transmission. We provide evidence that TORC1 is involved in L-LTP maintenance at the Schaffer collateral-CA1 synapses in the hippocampus.BDNF ͉ calcineurin ͉ cAMP-response element-binding protein ͉ long-term potentiation ͉ memory T ransducers of regulated cAMP-response element-binding protein (CREB) activity (TORCs) are newly discovered coactivators that dramatically increase CREB's transcriptional activity independently of CREB Ser-133 phosphorylation (1, 2). Recently, it has been shown that TORC2 functions as a pancreatic coincidence detector. In insulinoma cells, glucose and gut hormones, via respective activation of L-type calcium channels and the cAMP pathway, synergistically promote the dephosphorylation and the concomitant nuclear translocation of TORC2 (3). In the brain, encoding and storing associative memories requires detection of the coincidence of different input signals and translation of these associations into changes in the number, structure, or function of synapses. Therefore, it appears that short-lived coincidences result in the transcriptional activation of genes encoding factors required for enhanced synaptic transmission. TORCs present two features that neurons could use to create an association: they can detect the coincidence of the two most important second messengers, calcium and cAMP, and they are potent coactivators of CREB, a transcription factor known to drive the expression of genes underlying synaptic plasticity, late-phase long-term potentiation (L-LTP), learning, and memory (4-7).CREB-dependent promoters have been generally thought to respond to various intracellular and extracellular cues by the stimulus-dependent phosphorylation of CREB at Ser-133 and resultant recruitment of the coactivator CREB binding protein (CBP) (5,6,8,9). Modification of CREB at this site often mirrors the activation of neurons, leading to the idea that the expression of plasticity-related genes relies on CREB/CBP interaction. However, some studies revealing a discrepancy between CREB phosphorylation and CREB-mediated gene transcription have challenged this model. For instance, monocular deprivation induces LacZ expression in the visual cortex of cAMP-response element (CRE)-LacZ transgenic mice (10), whereas phosphorylation of CREB at Ser-133 remains static (11). Similarly, the mechanism underlying CREB activation during L...

“…In the last several years, the peroxisome proliferator activated receptor coactivator (PGC)-1␣/␤ and liver X receptor (LXR)/sterol response element-binding protein (SREBP) have been identified as key transcriptional regulators of many metabolic enzymes and pathways (18)(19)(20). The PGC-1␣ transcriptional network is the target of hormonal and nutrient signals.…”

mentioning

confidence: 99%

Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1

Rodgers

Puigserver

2007

482

447

In the fasted state, induction of hepatic glucose output and fatty acid oxidation is essential to sustain energetic balance. Production and oxidation of glucose and fatty acids by the liver are controlled through a complex network of transcriptional regulators. Among them, the transcriptional coactivator PGC-1␣ plays an important role in hepatic and systemic glucose and lipid metabolism. We have previously demonstrated that sirtuin 1 (SIRT1) regulates genes involved in gluconeogenesis through interaction and deacetylation of PGC-1␣. Here, we show in vivo that hepatic SIRT1 is a factor in systemic and hepatic glucose, lipid, and cholesterol homeostasis. Knockdown of SIRT1 in liver caused mild hypoglycemia, increased systemic glucose and insulin sensitivity, and decreased glucose production. SIRT1 knockdown also decreased serum cholesterol and increased hepatic free fatty acid and cholesterol content. These metabolic phenotypes caused by SIRT1 knockdown tightly correlated with decreased expression of gluconeogenic, fatty acid oxidation and cholesterol degradation as well as efflux genes. Additionally, overexpression of SIRT1 reversed many of the changes caused by SIRT1 knockdown and depended on the presence of PGC-1␣. Interestingly, most of the effects of SIRT1 were only apparent in the fasted state. Our results indicate that hepatic SIRT1 is an important factor in the regulation of glucose and lipid metabolism in response to nutrient deprivation. As these pathways are dysregulated in metabolic diseases, SIRT1 may be a potential therapeutic target to control hyperglycemia and hypercholesterolemia.fasting response ͉ glucose metabolism ͉ lipid metabolism ͉ deacetylase ͉ transcriptional coactivator