scholarly journals The Phosphorylation Status of a Cyclic AMP-Responsive Activator Is Modulated via a Chromatin-Dependent Mechanism

2000 ◽  
Vol 20 (5) ◽  
pp. 1596-1603 ◽  
Author(s):  
Laura F. Michael ◽  
Hiroshi Asahara ◽  
Andrew I. Shulman ◽  
W. Lee Kraus ◽  
Marc Montminy
Keyword(s):  
Cyclic Amp ◽  
Target Gene ◽  
Regulatory Mechanism ◽  
Gene Activation ◽  
Hdac Inhibitors ◽  
Histone Acetyltransferases ◽  
Creb Binding Protein ◽  
Creb Phosphorylation ◽  
P300 Recruitment ◽  
Dependent Mechanism

ABSTRACT Cyclic AMP (cAMP) stimulates the expression of numerous genes via the protein kinase A (PKA)-mediated phosphorylation of CREB at Ser133. Ser133 phosphorylation, in turn, promotes recruitment of the coactivator CREB binding protein and its paralog p300, histone acetyltransferases (HATs) that have been proposed to mediate target gene activation, in part, by destabilizing promoter bound nucleosomes and thereby allowing assembly of the transcriptional apparatus. Here we show that although histone deacetylase (HDAC) inhibitors potentiate target gene activation via cAMP, they do not stimulate transcription over the early burst phase, during which CREB phosphorylation and CBP/p300 recruitment are maximal. Rather, HDAC inhibitors augment CREB activity during the late attenuation phase by prolonging CREB phosphorylation on chromosomal but, remarkably, not on extrachromosomal templates. In reconstitution studies, assembly of periodic nucleosomal arrays on a cAMP-responsive promoter template potently inhibited CREB phosphorylation by PKA, and acetylation of these template-bound nucleosomes by p300 partially rescued CREB phosphorylation by PKA. Our results suggest a novel regulatory mechanism by which cellular HATs and HDACs modulate the phosphorylation status of nuclear activators in response to cellular signals.

scholarly journals Characterization of a CREB Gain-of-Function Mutant with Constitutive Transcriptional Activity In Vivo

2000 ◽  
Vol 20 (12) ◽  
pp. 4320-4327 ◽  
Author(s):  
Keyong Du ◽  
Hiroshi Asahara ◽  
Ulupi S. Jhala ◽  
Brandee L. Wagner ◽  
Marc Montminy
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Rna Polymerase Ii ◽  
Target Gene ◽  
Gene Activation ◽  
Creb Binding Protein ◽  
Cellular Gene ◽  
Creb Phosphorylation ◽  
Additional Signal

ABSTRACT The cyclic AMP (cAMP)-responsive factor CREB promotes cellular gene expression, following its phosphorylation at Ser133, via recruitment of the coactivator paralogs CREB-binding protein (CBP) and p300. CBP and p300, in turn, appear to mediate target gene induction via their association with RNA polymerase II complexes and via intrinsic histone acetyltransferase activities that mobilize promoter-bound nucleosomes. In addition to cAMP, a wide variety of stimuli, including hypoxia, UV irradiation, and growth factor addition, induce Ser133 phosphorylation with stoichiometry and kinetics comparable to those induced by cAMP. Yet a number of these signals are incapable of promoting target gene activation via CREB phosphorylation per se, suggesting the presence of additional regulatory events either at the level of CREB-CBP complex formation or in the subsequent recruitment of the transcriptional apparatus. Here we characterize a Tyr134Phe CREB mutant that behaves as a constitutive activator in vivo. Like protein kinase A (PKA)-stimulated wild-type CREB, the Tyr134Phe polypeptide was found to stimulate target gene expression via the Ser133-dependent recruitment of CBP and p300. Biochemical studies reveal that mutation of Tyr134 to Phe lowers the Km for PKA phosphorylation and thereby induces high levels of constitutive Ser133 phosphorylation in vivo. Consistent with its constitutive activity, Tyr134Phe CREB strongly promoted differentiation of PC12 cells in concert with suboptimal doses of nerve growth factor. Taken together, these results demonstrate that Ser133 phosphorylation is sufficient for cellular gene activation and that additional signal-dependent modifications of CBP or p300 are not required for recruitment of the transcriptional apparatus to the promoter.

CREB-binding protein (CREBBP) and preeclampsia: a new promising target gene

2021 ◽  
Vol 48 (3) ◽  
pp. 2117-2122
Author(s):  
Hossein Sadeghi ◽  
Sahra Esmkhani ◽  
Reihaneh Pirjani ◽  
Mona Amin-Beidokhti ◽  
Milad Gholami ◽  
...  
Keyword(s):  
Target Gene ◽  
Binding Protein ◽  
Creb Binding Protein ◽  
Promising Target

scholarly journals FGF16 regulated by miR-520b enhances the cell proliferation of lung cancer

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 419-427
Author(s):  
Wenfeng He ◽  
Xia Liu ◽  
Zhijie Luo ◽  
Longmei Li ◽  
Xisheng Fang
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Untranslated Region ◽  
Target Gene ◽  
Regulatory Mechanism ◽  
The Novel ◽  
Accelerated Growth ◽  
High Level ◽  
Cancer Tissues ◽  
Great Damage

Abstract FGF16 is implicated in the progression of some specific types of cancers, such as embryonic carcinoma, ovarian cancer, and liver cancer. Yet, the function of FGF16 in the development of lung cancer remains largely unexplored. In this study, we present the novel function of FGF16 and the regulation of miR-520b on FGF16 in lung cancer progression. In clinical lung cancer tissues, FGF16 is overexpressed and its high level is negatively associated with the low level of miR-520b. Furthermore, both the transcription and translation levels of FGF16 are restrained by miR-520b in lung cancer cells. For the regulatory mechanism investigation, miR-520b is able to directly bind to the 3′-untranslated region (3′UTR) of FGF16 mRNA, leading to its mRNA cleavage in the cells. Functionally, miR-520b reduces the growth of lung cancer and its inhibitor anti-miR520b is able to promote the growth through competing endogenous miR-520b. Moreover, FGF16 silence using RNA interference is capable of doing great damage to anti-miR-520b-accelerated growth of lung cancer. Thus, our finding indicates that FGF16 is a new target gene of miR-520b in lung cancer. For lung cancer, FGF16 may serve as a novel biomarker and miR-520b/FGF16 may be useful in clinical treatment.

scholarly journals FBXW7 mutations reduce binding of NOTCH1, leading to cleaved NOTCH1 accumulation and target gene activation in CLL

Blood ◽  
2019 ◽  
Vol 133 (8) ◽  
pp. 830-839 ◽  
Author(s):  
Viola Close ◽  
William Close ◽  
Sabrina Julia Kugler ◽  
Michaela Reichenzeller ◽  
Deyan Yordanov Yosifov ◽  
...  
Keyword(s):  
Target Gene ◽  
Hypoxia Inducible Factor ◽  
Gene Activation ◽  
Lymphocytic Leukemia ◽  
Negative Regulator ◽  
Missense Mutations ◽  
Protein Levels ◽  
In Silico Modeling ◽  
Functional Consequences ◽  
Wd40 Domain

Abstract NOTCH1 is mutated in 10% of chronic lymphocytic leukemia (CLL) patients and is associated with poor outcome. However, NOTCH1 activation is identified in approximately one-half of CLL cases even in the absence of NOTCH1 mutations. Hence, there appear to be additional factors responsible for the impairment of NOTCH1 degradation. E3-ubiquitin ligase F-box and WD40 repeat domain containing-7 (FBXW7), a negative regulator of NOTCH1, is mutated in 2% to 6% of CLL patients. The functional consequences of these mutations in CLL are unknown. We found heterozygous FBXW7 mutations in 36 of 905 (4%) untreated CLL patients. The majority were missense mutations (78%) that mostly affected the WD40 substrate binding domain; 10% of mutations occurred in the first exon of the α-isoform. To identify target proteins of FBXW7 in CLL, we truncated the WD40 domain in CLL cell line HG-3 via clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9). Homozygous truncation of FBXW7 resulted in an increase of activated NOTCH1 intracellular domain (NICD) and c-MYC protein levels as well as elevated hypoxia-inducible factor 1-α activity. In silico modeling predicted that novel mutations G423V and W425C in the FBXW7-WD40 domain change the binding of protein substrates. This differential binding was confirmed via coimmunoprecipitation of overexpressed FBXW7 and NOTCH1. In primary CLL cells harboring FBXW7 mutations, activated NICD levels were increased and remained stable upon translation inhibition. FBXW7 mutations coincided with an increase in NOTCH1 target gene expression and explain a proportion of patients characterized by dysregulated NOTCH1 signaling.

scholarly journals Effects of H3 and H4 Histones Acetylation and Bindings of CREB Binding Protein and p300 at the Promoter on Hepatic Expression of γ-glutamyltransferase Gene in a Streptozotocin-Induced Moderate Hypoinsulinemic Rat Model

2021 ◽  
pp. 475-480
Author(s):  
T TANAKA ◽  
T MIZUNO ◽  
T NAKAGAWA ◽  
T HAYAKAWA ◽  
M SHIMADA
Keyword(s):  
Insulin Secretion ◽  
Rat Model ◽  
Binding Protein ◽  
Histone Acetyltransferases ◽  
Creb Binding Protein ◽  
Concerted Effort ◽  
Promoter Regions ◽  
Gamma Glutamyltransferase ◽  
Hepatic Expression ◽  
Increased Risk

Gamma-glutamyltransferase (GGT), a marker of liver disease, has been shown to be associated with increased risk of diabetes and relative insulin secretion deficiency. However, the mechanism of hepatic Ggt regulation has not been explored fully. In this study, we made a concerted effort to understand the mechanism by investigating the effects of acetylation of histones H3 and H4, and bindings of histone acetyltransferases, CREB binding protein (CBP) and p300, at the Ggt promoter on the regulation of the expression of Ggt gene in the livers of streptozotocin (STZ)-induced moderate hypoinsulinemia rat model. The rats treated with STZ showed remarkably higher serum GGT level and hepatic Ggt/GGT expression than the untreated control rats. Furthermore, the acetylation of histones H3 and H4, and the binding of CBP not p300 at the Ggt promoter regions were significantly higher in the livers of STZ rats than those of the control rats. These results suggest that an enhanced hepatic expression of Ggt is associated with increased acetylation of histones H3 and H4 and CBP binding at the Ggt promoter in STZ-induced moderate hypoinsulinemic rats.

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