Individual CREB-target genes dictate usage of distinct cAMP-responsive coactivation mechanisms

Xu, Wu; Kasper, Lawryn H.; Lerach, Stephanie; Jeevan, Trushar; Brindle, Paul K.

doi:10.1038/sj.emboj.7601734

Cited by 115 publications

(126 citation statements)

References 52 publications

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“…In further support of normal Rhokinase activity in the absence of Mdm2, we observed no differences in serine 133 phosphorylation of CREB in p53 À/À and p53 À/À ;mdm2 À/À MEFs upon induction of adipogenesis (Supplementary Figure 7). Although CREB phosphorylation was comparable in MEFs of both genotypes, the induction of several cAMP-responsive CREB target genes 8,30 was perturbed in p53 À/À ;mdm2 À/À MEFs upon IBMX treatment (Figure 4a). We therefore speculated whether Mdm2 could be a direct modulator of CREB activity.…”

Section: Resultsmentioning

confidence: 99%

“…The Crtcs solely coactivate CREB bound to genes regulated by cAMP 9 by facilitating the recruitment of the two histone acetylases p300 and CBP to CREB. 8,9 Under basal conditions, Crtc is localized to the cytoplasm as a result of a phosphorylation-dependent interaction with 14-3-3 proteins, mediated by members of the salt-inducible kinase (SIK) family. Upon elevated cAMP levels, PKA inhibits the SIKs, leading to dephosphorylation and translocation of Crtc to the nucleus and subsequent coactivation of CREB.…”

Section: Resultsmentioning

confidence: 99%

“…[4][5][6] The recent cloning and characterization of a CREB cofactor family, denoted as CREB-regulated transcription coactivator (Crtc/TORC), have revealed how CREB can induce expression of distinct target genes dependent on different stimuli. [7][8][9] The murine double minute 2 (Mdm2) is an E3 ubiquitin ligase with oncogenic properties. Its importance in the control of p53 activity is underscored by the finding that knockout of p53 rescues the embryonic lethality of mice lacking mdm2.…”

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Mdm2 controls CREB-dependent transactivation and initiation of adipocyte differentiation

et al. 2012

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The role of the E3 ubiquitin ligase murine double minute 2 (Mdm2) in regulating the stability of the p53 tumor suppressor is well documented. By contrast, relatively little is known about p53-independent activities of Mdm2 and the role of Mdm2 in cellular differentiation. Here we report a novel role for Mdm2 in the initiation of adipocyte differentiation that is independent of its ability to regulate p53. We show that Mdm2 is required for cAMP-mediated induction of CCAAT/enhancer-binding protein d (C/EBPd) expression by facilitating recruitment of the cAMP regulatory element-binding protein (CREB) coactivator, CREB-regulated transcription coactivator (Crtc2)/TORC2, to the c/ebpd promoter. Our findings reveal an unexpected role for Mdm2 in the regulation of CREB-dependent transactivation during the initiation of adipogenesis. As Mdm2 is able to promote adipogenesis in the myoblast cell line C2C12, it is conceivable that Mdm2 acts as a switch in cell fate determination.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Mdm2 controls CREB-dependent transactivation and initiation of adipocyte differentiation

et al. 2012

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“…Ectopic expression of TORCs bypasses normal regulatory mechanisms and activates reporter genes many hundredfold, suggesting that TORCs either have intrinsic enzymatic activity or recruit catalytic proteins. Recent studies demonstrate that TORC2 mediates target gene activation in response to cAMP in part by cooperative interactions with CBP (14,15); however, CBP/p300 recruitment cannot fully explain how TORCs robustly activate transcription. Moreover, the contribution of each of these coactivators varies, depending on the cAMP-responsive promoter (15).…”

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confidence: 99%

A coactivator trap identifies NONO (p54 ^nrb ) as a component of the cAMP-signaling pathway

Amelio¹,

Miraglia

Conkright

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

105

117

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Signal transduction pathways often use a transcriptional component to mediate adaptive cellular responses. Coactivator proteins function prominently in these pathways as the conduit to the basic transcriptional machinery. Here we present a high-throughput cell-based screening strategy, termed the ''coactivator trap,'' to study the functional interactions of coactivators with transcription factors. We applied this strategy to the cAMP signaling pathway, which utilizes two families of coactivators, the cAMP response element binding protein (CREB) binding protein (CBP)/p300 family and the recently identified transducers of regulated CREB activity family (TORCs1-3). In addition to identifying numerous known interactions of these coactivators, this analysis identified NONO (p54 nrb ) as a TORC-interacting protein. RNA interference experiments demonstrate that NONO is necessary for cAMP-dependent activation of CREB target genes in vivo. Furthermore, TORC2 and NONO complex on cAMP-responsive promoters, and NONO acts as a bridge between the CREB/TORC complex and RNA polymerase II. These data demonstrate the utility of the coactivator trap by identification of a component of cAMP-mediated transcription.transcription ͉ signal transduction ͉ cell-based screen ͉ RNA polymerase II ͉ transducer of regulated cAMP response element-binding protein T ranscription is regulated by large multisubunit complexes that can be grouped into three general categories; DNA binding proteins, coregulators (coactivators and corepressors), and basal transcriptional components. DNA binding proteins recognize discrete sequences or response elements within promoters and in general function as scaffolds that direct the recruitment of coregulatory proteins. Coregulators in turn function as a conduit to the basic transcriptional machinery. Coregulators may also influence gene expression via intrinsic enzymatic activity or by recruitment of other enzyme activities (e.g., acetylation, methylation, poly ADPribosylation, ubiquitination, sumoylation, or ATP-dependent remodeling complexes) capable of modifying both transcriptional proteins and chromatin (1). Thus, determining the interaction networks of coregulators recruited by transcription factors and the accompanying enzymatic activities is necessary for understanding the complexities of gene expression.The cAMP signal-transduction pathway activates transcription by stimulating interactions between cAMP response element binding protein (CREB) and two coactivator families, CREBbinding protein (CBP)/p300 and transducers of regulated CREB (TORCs) (2-4). CREB-CBP/p300 interaction occurs when elevations in intracellular cAMP liberate protein kinase A (PKA) catalytic subunits (PKA c ) from PKA regulatory subunits. PKA c directly phosphorylates serine 133 in the kinase-inducible domain of CREB, increasing the affinity of CBP/p300 for CREB (5, 6). CBP/p300 interacts with components of the RNA polymerase II (RNA pol II) complex to facilitate transcription and contains intrinsic acetyltransferase activity specula...

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“…CREB is a critical mediator of cAMP‐ and calcium‐inducible transcription, whereas the phosphorylation of serine 133 (phospho‐Ser133) in its kinase‐inducible domain (KID) is its main transactivating form. Phospho‐Ser133 plays a role in CREB to bind the KIX domain of the coactivators CBP and p300 (CBP/p300) 50. Vecsey et al25 demonstrated that enhancement of hippocampus‐dependent memory and synaptic plasticity by HDAC inhibitors was relied on the binding of CREB and CREB‐binding protein (CBP), which induced robust activation of gene transcription afterwards.…”

Section: Discussionmentioning

confidence: 99%

Propofol exposure during early gestation impairs learning and memory in rat offspring by inhibiting the acetylation of histone

Lin

Wang

Feng

et al. 2018

J Cellular Molecular Medi

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Propofol is widely used in clinical practice, including non‐obstetric surgery in pregnant women. Previously, we found that propofol anaesthesia in maternal rats during the third trimester (E18) caused learning and memory impairment to the offspring rats, but how about the exposure during early pregnancy and the underlying mechanisms? Histone acetylation plays an important role in synaptic plasticity. In this study, propofol was administered to the pregnant rats in the early pregnancy (E7). The learning and memory function of the offspring were tested by Morris water maze (MWM) test on post‐natal day 30. Two hours before each MWM trial, histone deacetylase 2 (HDAC2) inhibitor, suberoylanilide hydroxamic acid (SAHA), Senegenin (SEN, traditional Chinese medicine), hippyragranin (HGN) antisense oligonucleotide (HGNA) or vehicle were given to the offspring. The protein levels of HDAC2, acetylated histone 3 (H3) and 4 (H4), cyclic adenosine monophosphate (cAMP) response element‐binding protein (CREB), N‐methyl‐D‐aspartate receptor (NMDAR) 2 subunit B (NR2B), HGN and synaptophysin in offspring's hippocampus were determined by Western blot or immunofluorescence test. It was discovered that infusion with propofol in maternal rats on E7 leads to impairment of learning and memory in offspring, increased the protein levels of HDAC2 and HGN, decreased the levels of acetylated H3 and H4 and phosphorylated CREB, NR2B and synaptophysin. HDAC2 inhibitor SAHA, Senegenin or HGN antisense oligonucleotide reversed all the changes. Thus, present results indicate exposure to propofol during the early gestation impairs offspring's learning and memory via inhibiting histone acetylation. SAHA, Senegenin and HGN antisense oligonucleotide might have therapeutic value for the adverse effect of propofol.

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Individual CREB-target genes dictate usage of distinct cAMP-responsive coactivation mechanisms

Cited by 115 publications

References 52 publications

Mdm2 controls CREB-dependent transactivation and initiation of adipocyte differentiation

Mdm2 controls CREB-dependent transactivation and initiation of adipocyte differentiation

A coactivator trap identifies NONO (p54 ^nrb ) as a component of the cAMP-signaling pathway

Propofol exposure during early gestation impairs learning and memory in rat offspring by inhibiting the acetylation of histone

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Individual CREB-target genes dictate usage of distinct cAMP-responsive coactivation mechanisms

Cited by 115 publications

References 52 publications

Mdm2 controls CREB-dependent transactivation and initiation of adipocyte differentiation

Mdm2 controls CREB-dependent transactivation and initiation of adipocyte differentiation

A coactivator trap identifies NONO (p54 nrb ) as a component of the cAMP-signaling pathway

Propofol exposure during early gestation impairs learning and memory in rat offspring by inhibiting the acetylation of histone

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A coactivator trap identifies NONO (p54 ^nrb ) as a component of the cAMP-signaling pathway