The cAMP response element binding protein, CREB, is a potent inhibitor of diverse transcriptional activators

Lemaigre, Frédéric P.; Christopher, I.; Green, Michael R.

doi:10.1093/nar/21.12.2907

Cited by 39 publications

(30 citation statements)

References 34 publications

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“…Although CREB is mostly described as a positive transcription factor, several reports have shown that it can also inhibit the transcription activity of diverse promoters such as those of c-fos, 38 5-amino-leavulinate synthase, 39 and somatostatin 40 genes. Lemaigre et al 41 showed that CREB, after dimerization, inhibits diverse transcriptional activators. Previous studies have also shown that Ang II inhibits adenylyl cyclase activity and intracellular accumulation of cAMP.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II–Mediated Negative Regulation of Npr1 Promoter Activity and Gene Transcription

Garg

Pandey

2003

Hypertension

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Abstract-Atrial natriuretic peptide receptor A (NPRA) plays important role(s) in the control of extracellular fluid volume and blood pressure homeostasis. We have determined and analyzed the functional promoter region of Npr1 gene (coding for NPRA) and studied the effect of angiotensin (Ang) II on its promoter activity and expression in cultured mouse mesangial cells. The promoter analysis of Npr1 gene revealed the presence of positive regulatory cis-elements in the regions Ϫ1982 to Ϫ1841 bp and Ϫ916 to Ϫ496 bp and of the repressor elements in the regions Ϫ1841 to Ϫ916 bp and 56 to 382 bp relative to transcription start site. The Ang II pretreatment of cultured mouse mesangial cells transiently transfected with the promoter construct pNPRA-luc1 significantly inhibited the promoter activity in a time-and dose-dependent manner, with a maximum inhibition at 24 hours. A trial natriuretic peptide (ANP) is a member of the natriuretic peptide family, which is comprised of ANP, brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), each derived from a separate gene. 1 ANP elicits a number of vascular, renal, and endocrine effects, resulting in the maintenance of blood pressure and extracellular fluid volume by binding to the specific cell surface receptors. [2][3][4][5] Three subtypes of natriuretic peptide receptors have been characterized, purified, and cloned, ie, natriuretic peptide receptors A, B, and C (also designated as NPRA, NPRB, and NPRC, respectively). 4,5 ANP specifically binds NPRA and NPRC, of which NPRA contains guanylyl cyclase catalytic activity and produces intracellular second-messenger cGMP in response to hormone binding, and NPRC lacks the guanylyl cyclase activity. NPRA is considered the biological receptor of ANP and BNP because most of the physiological effects of these peptide hormones are triggered by generation of cGMP or its cell-permeable analogs. 6 The activity and expression of NPRA, assessed primarily through ANPdependent guanylyl cyclase activity and cGMP accumulation, are regulated by a number of factors, including ANP itself, 7-9 other hormones such as glucocorticoids 10 and angiotensin (Ang) II, 11-13 growth factors, 14,15 pathophysiological conditions, 16,17 and changes in extracellular ion composition. 18,19 The peptide hormone Ang II is an important component of renin-angiotensin system and exerts its biological effects such as blood pressure control, vasoconstriction, and cell proliferation in many tissues, including in the kidney, adrenal glands, brain, and vasculature. The 2 vasoactive peptide hormones Ang II (vasoconstrictive) and ANP (vasodilatory) interact and mutually antagonize the physiological effects of each other at various levels. For example, ANP has been reported to inhibit Ang II-induced contraction of isolated glomeruli and cultured mesangial cells. 20 ANP also inhibits Ang II-stimulated activation of protein kinase C and mitogen-activated protein kinase in vascular smooth muscle and mesangial cells in a cGMP-dependent manner. 21,22 Furthermore, AN...

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Section: Discussionmentioning

confidence: 99%

Angiotensin II–Mediated Negative Regulation of Npr1 Promoter Activity and Gene Transcription

Garg

Pandey

2003

Hypertension

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“…Accordingly, CREB is activated via phosphorylation induced by several distinct signals (protein kinase A [PKA], Ca2+, and transforming growth factor 1) (12,22,30,48) and through interactions with cell-specific transcription factors (4,40). In addition to acting as an inducible activator, CREB can function as a constitutive activator (36) or as a potent inhibitor of a diverse class of transcriptional activators (35). The molecular mechanisms that allow CREB to act in such a malleable manner are poorly understood.…”

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confidence: 99%

A monomeric derivative of the cellular transcription factor CREB functions as a constitutive activator.

Lee¹

1994

Mol. Cell. Biol.

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The mammalian transcriptional activator CREB binds as a dimer to a broad spectrum of inducible promoters. CREB activity is modulated by several signalling agents (protein kinase A [PKA], Ca2 , and transforming growth factor 0) and via functional interactions with cell-specific transcription factors. In addition, CREB can activate transcription constitutively and repress the activity of several other transcriptional activators. The mechanisms that allow CREB to act in such a malleable manner and the role that CREB dimerization might play in this are poorly understood. To probe the latter issue, we have created monomeric forms of CREB by fusing CREB to the DNA-binding domain of a protein (B-cell specific activator protein [BSAP]) that binds to DNA as a monomer. Remarkably, monomeric CREB acts as a potent, constitutive activator under conditions in which native CREB is inducible by PKA. Thus, CREB contains constitutive activation regions that are unable to function in native CREB. Two glutamine-rich domains that are important for native, PKA-inducible CREB activity are required for the constitutive activity of monomeric CREB. In contrast, two elements within the kinase-inducible domain of CREB are dispensable for constitutive activity.We discuss our results in relation to inducible and constitutive CREB activity and the potential modes of action of other activators that directly interact with CREB.The bZIP family of transcription factors bind to DNA as dimers and activate or repress transcription of a variety of mammalian promoters. The bZIP domain is responsible for dimerization and DNA binding and consists of a leucine zipper structure (ZIP) that mediates dimerization and an adjacent basic region (b) that directly contacts DNA (2, 6, 54). The cyclic AMP (cAMP) response element-binding protein (CREB) is one of the best-characterized bZIP proteins. CREB is implicated in a host of biological functions, including neuronal excitation (10), setting of circadian rhythms (20), pituitary proliferation (49), gluconeogenesis (4), and opiate tolerance (23). Accordingly, CREB is activated via phosphorylation induced by several distinct signals (protein kinase A [PKA], Ca2+, and transforming growth factor 1) (12,22,30,48) and through interactions with cell-specific transcription factors (4,40). In addition to acting as an inducible activator, CREB can function as a constitutive activator (36) or as a potent inhibitor of a diverse class of transcriptional activators (35). The molecular mechanisms that allow CREB to act in such a malleable manner are poorly understood.The role of CREB in cAMP signalling has provided the main focus for studying CREB (34). PKA activates CREB by direct phosphorylation of a single serine (22). In addition to the PKA phosphoacceptor site (Ser-119), several other regions of CREB are required for transcriptional activation (see Fig. 1). The PKA site is part of the kinase-inducible domain (KID) (21, 32), which contains an element termed 1 (21, 32), an a-helical region (a2), and a protein kinase C (PKC) ...

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“…Interestingly, both the wt and a dominant-negative CREB mutant inhibited the IL-2 promoter activity, suggesting that CREB may be acting and inhibiting as a part of a protein complex, rather than directly binding to the target sequence. It was indeed reported previously that CREB can serve as a repressor of various promoters and this function is not associated with CRE element binding or activator binding (20). One possibility is that binding of CREB or CREB-containing complexes prevents binding or assembly of other activating complexes, which exhibit higher affinity for the SM-derived sequence; however, the inhibitory effect of CREB per se is independent of the differences in sequence between the species.…”

Section: Discussionmentioning

confidence: 92%

“…The construct pIL2PSMDBL was obtained similarly by first generating 5Ј and 3Ј parts of the SM-proximal promoter using primers 5Ј-CTGACAGAATGGATGACCCCCAAAGACTGACA-3Ј and 5Ј-CATCCATTCTGTCAGTCTTTGGGGGT-3Ј together with IL2PU or IL2PD and subsequent PCR splicing, as above, leading to a duplication of the Ϫ180 site from SM. The plasmids expressing CREB and dominantnegative A-CREB were gifts from M. Green (University of Massachusetts, Worcester, MA) and C. Vinson (National Cancer Institute, Bethesda, MD) (20,21). Plasmids expressing p300 were a gift from K. Gardner (22).…”

Section: Il-2 Promoter Constructs and Transfectionsmentioning

confidence: 99%

CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys Produce More IL-2 Than Cells from Disease-Susceptible Species: Involvement of p300 and CREB at the Proximal IL-2 Promoter in IL-2 Up-Regulation

Boštík

Noble

Stephenson

et al. 2007

The Journal of Immunology

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IL-2 is an important cytokine required for the physiological function of CD4+ T cells. Immunological unresponsiveness—anergy— of CD4+ T cells is characterized by the inability of these cells to synthesize IL-2. Both progressive HIV infection leading to AIDS in humans and SIV infection in rhesus macaques (RM) are associated with dysregulation of IL-2 synthesis. In certain nonhuman primate species, such as sooty mangabeys (SM), SIV infection does not lead to AIDS. We have shown that this is associated with the resistance of the CD4+ T cells from SM to undergo anergy in vitro. In this study, we show that CD4+ T cells from SM spontaneously synthesize 2- to 3-fold higher levels of IL-2 than corresponding cells from RM. Proximal IL-2 promoter constructs derived from SM show significantly higher activity than the RM-derived constructs in primary CD4+ T cells, which is associated with an element at approximately nt −200. Activity of both constructs was up-regulated by p300 and down-regulated by CREB to a similar degree. Chromatin immunoprecipitation analysis showed significantly higher binding of p300 and lower binding of CREB to the SM promoter in vivo. Two single nucleotide substitutions present in the SM sequence around position −200 and −180 seem to increase the affinity of these sites for the binding of transcription factors, one of which was identified as Oct-1. These unique characteristics of the proximal IL-2 promoter in SM therefore can represent one of the mechanisms contributing to the resistance of these cells to undergo anergy.

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The cAMP response element binding protein, CREB, is a potent inhibitor of diverse transcriptional activators

Cited by 39 publications

References 34 publications

Angiotensin II–Mediated Negative Regulation of Npr1 Promoter Activity and Gene Transcription

Angiotensin II–Mediated Negative Regulation of Npr1 Promoter Activity and Gene Transcription

A monomeric derivative of the cellular transcription factor CREB functions as a constitutive activator.

CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys Produce More IL-2 Than Cells from Disease-Susceptible Species: Involvement of p300 and CREB at the Proximal IL-2 Promoter in IL-2 Up-Regulation

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