Attenuation of a phosphorylation-dependent activator by an HDAC–PP1 complex

Canettieri, Gianluca; Morantte, Ianessa; Guzmán, Ernesto; Asahara, Hiroshi; Herzig, Stephan; Anderson, Scott; Yates, John R.; Montminy, Marc

doi:10.1038/nsb895

Cited by 180 publications

(174 citation statements)

References 41 publications

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“…In fact, it is known that PP1 does not have good substrate specificity, and that the PP1-interacting proteins not only localize PP1 to different cellular compartments, but can also deliver PP1 to close proximity of potential substrates, increasing PP1 substrate specificity and catalytic efficiency (Hu et al, 2006). Consistently, it has been recently reported that HDAC1 interacts with PP1 and is critical for the efficient action of PP1 on CREB1 (Canettieri et al, 2003). These data and the interaction between PP1 and CCDC6, showed in our experiments, suggested a possible interaction also between HDAC1 and CCDC6 that we have analyzed and confirmed.…”

Section: Ccdc6 Represses Creb1 Activitymentioning

confidence: 96%

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CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

et al. 2010

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RET/papillary thyroid carcinoma 1 (PTC1) oncogene is frequently activated in human PTCs. It is characterized by the fusion of the intracellular kinase-encoding domain of RET to the first 101 amino acids of CCDC6. The aim of our work is to characterize the function of the CCDC6 protein to better understand the function of its truncation, that results in the loss of the expression of one allele, in the process of thyroid carcinogenesis. Here, we report that CCDC6 interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 and protein phosphatase 1 proteins at the CRE site of the CREB1 target genes. Finally, we show an increased CREB1 phosphorylation and activity in PTCs carrying the RET/PTC1 oncogene. Consistently, an increased expression of two known CREB1 target genes, AREG and cyclin A, was observed in this subgroup of thyroid papillary carcinomas. Therefore, the repression of CREB1 activity by CCDC6 has a critical function in the development of human thyroid papillary carcinomas carrying RET/PTC1 activation.

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Section: Ccdc6 Represses Creb1 Activitymentioning

confidence: 96%

“…Recently, it has been shown that PP1 can be targeted to CREB1, for efficient dephosphorylation, through binding of PP1 to HDAC1 (Canettieri et al, 2003) or HDAC8 proteins (Gao et al, 2009). HDACs catalyze the removal of acetyl groups from core histones (Marks et al, 2001), inducing local condensation of chromatin.…”

Section: Ccdc6 Physically Interacts With Hdac1mentioning

confidence: 99%

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

et al. 2010

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“…Reduced PP1 may have important effects for transcriptional regulation by CREB through the ability of PP1 to complex with HDAC. Canettieri et al (2003) demonstrated that a HDAC1-PP1 complex represses CREB activation under basal conditions and dephosphorylates CREB to return the system to baseline after a stimulus. This suggests that repression of PP1 is crucial in providing phosphorylated CREB with the capacity to recruit CBP to the promoter, at which time histones become acetylated and help to drive the transcription of particular genes.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Regulates Cocaine-Induced Behavioral Sensitization in Mice

Anier

Malinovskaja

Aonurm-Helm

et al. 2010

Neuropsychopharmacol

189

170

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The behavioral sensitization produced by repeated cocaine treatment represents the neural adaptations underlying some of the features of addiction in humans. Cocaine administrations induce neural adaptations through regulation of gene expression. Several studies suggest that epigenetic modifications, including DNA methylation, are the critical regulators of gene expression in the adult central nervous system. DNA methylation is catalyzed by DNA methyltransferases (DNMTs) and consequent promoter region hypermethylation is associated with transcriptional silencing. In this study a potential role for DNA methylation in a cocaine-induced behavioral sensitization model in mice was explored. We report that acute cocaine treatment caused an upregulation of DNMT3A and DNMT3B gene expression in the nucleus accumbens (NAc). Using methylated DNA immunoprecipitation, DNA bisulfite modification, and chromatin immunoprecipitation assays, we observed that cocaine treatment resulted in DNA hypermethylation and increased binding of methyl CpG binding protein 2 (MeCP2) at the protein phosphatase-1 catalytic subunit (PP1c) promoter. These changes are associated with transcriptional downregulation of PP1c in NAc. In contrast, acute and repeated cocaine administrations induced hypomethylation and decreased binding of MeCP2 at the fosB promoter, and these are associated with transcriptional upregulation of fosB in NAc. We also found that pharmacological inhibition of DNMT by zebularine treatment decreased cocaine-induced DNA hypermethylation at the PP1c promoter and attenuated PP1c mRNA downregulation in NAc. Finally, zebularine and cocaine co-treatment delayed the development of cocaine-induced behavioral sensitization. Together, these results suggest that dynamic changes of DNA methylation may be an important gene regulation mechanism underlying cocaine-induced behavioral sensitization.

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“…The proximal promoter region of follistatin, containing MyoD-, CREBand NFAT-responsive elements, regulates muscle-restricted expression of follistatin 8 . Selective association of MyoD and CREB with class I histone deacetylases (HDACs) represses downstream gene transcription 13,14 , and only the class I HDACs HDAC1 and HDAC2 occupied the chromatin of the proximal follistatin promoter in myoblasts (Fig. 2e).…”

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confidence: 99%

Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors

Minetti

Colussi

Adami

et al. 2006

Nat Med

289

252

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Pharmacological interventions that increase myofiber size counter the functional decline of dystrophic muscles 1,2 . We show that deacetylase inhibitors increase the size of myofibers in dystrophin-deficient (MDX) and a-sarcoglycan (a-SG)-deficient mice by inducing the expression of the myostatin antagonist follistatin 3 in satellite cells. Deacetylase inhibitor treatment conferred on dystrophic muscles resistance to contraction-coupled degeneration and alleviated both morphological and functional consequences of the primary genetic defect. These results provide a rationale for using deacetylase inhibitors in the pharmacological therapy of muscular dystrophies.Enlarging fiber size in dystrophic muscles produces beneficial effects in dystrophin-deficient MDX mice, a model of Duchenne muscular dystrophy (DMD) 2,4-6 . Previous studies have shown that three structurally unrelated deacetylase inhibitors-trichostatin A (TSA), valproic acid (VPA) and phenylbutyrate (PhB)-share the ability to promote myoblast fusion into hypernucleated myotubes with an increased size relative to myotubes formed in the absence of drugs 7,8 . To select a compound for long-term treatment of dystrophic mice, we compared the results of pilot experiments in which MDX mice were exposed to TSA (0.6 mg per kg body weight per day), VPA (160 mg/kg per day) or PhB (90 mg/kg per day) by daily intraperitoneal injections. We chose to begin the treatment when the first manifestations of the disease were already evident, as we sought to evaluate the efficacy of deacetylase inhibitors in a situation simulating the clinical stage at which human patients typically receive the diagnosis of muscular dystrophy 9 . Increased histone acetylation, which reflects the bioactivity of deacetylase inhibitors, was detected in muscles and other peripheral organs (for example, brain) a few hours after injection, indicating rapid uptake of the compounds (Supplementary Figure 1 online). We next evaluated the ability of satellite cells from MDX mice exposed to the deacetylase inhibitors for 10 d to differentiate into multinucleated myotubes. After 24 h in differentiation medium, myotubes were present only in cultures of satellite cells isolated from mice exposed to deacetylase inhibitors (Supplementary Figure 2 online). Notably, satellite cells derived from TSA-treated mice formed myotubes with the highest efficiency and showed an increased expression, relative to that in untreated controls, of myosin heavy chain (MyHC)-a marker of terminal differentiation-and of regeneration markers, such as follistatin and embryonic and perinatal MyHC (Supplementary Figure 2). Only satellite cells from TSA-treated mice showed reduced levels of myostatin mRNA relative to those from untreated controls. Treatment of 12-week-old mice with deacetylase inhibitors for an additional three months prevented an increase in serum concentrations of creatine kinase, a biomarker for the severity of the disease (Supplementary Figure 2). The decline of creatine kinase concentrations was more pronounced i...

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Attenuation of a phosphorylation-dependent activator by an HDAC–PP1 complex

Cited by 180 publications

References 41 publications

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

DNA Methylation Regulates Cocaine-Induced Behavioral Sensitization in Mice

Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors

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