Ankyrin repeats-containing cofactors interact with ADA3 and modulate its co-activator function

2008 ◽  
Vol 413 (2) ◽  
pp. 349-357 ◽  
Author(s):  
Chia-Wei Li ◽  
Gia Khanh Dinh ◽  
Aihua Zhang ◽  
J. Don Chen
Keyword(s):  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Transactivation Domain ◽  
Ankyrin Repeats ◽  
Camp Response Element ◽  
Element Binding Protein

ANCO (ankyrin repeats-containing cofactor)-1 and ANCO-2 are a family of unique transcriptional co-regulators with dual properties: they interact with both the co-activators and the co-repressors [Zhang, Yeung, Li, Tsai, Dinh, Wu, Li and Chen (2004) J. Biol. Chem. 279, 33799–33805]. Specifically, ANCO-1 is thought to recruit HDACs (histone deacetylases) to the p160 co-activator to repress transcriptional activation by nuclear receptors. In the present study, we provide new evidence to suggest further that ANCO-1 and ANCO-2 also interact with the co-activator ADA3 (alteration/deficiency in activation 3). The interaction occurs between the conserved C-terminal domain of ANCO-1 and the N-terminal transactivation domain of ADA3. Several subunits of the P/CAF {p300/CBP [CREB (cAMP-response-element-binding protein)-binding protein]-associated factor} complex, including ADA3, ADA2α/β and P/CAF, showed co-localization with ANCO-1 nuclear dots, indicating an in vivo association of ANCO-1 with the P/CAF complex. Furthermore, a transient reporter assay revealed that both ANCO-1 and ANCO-2 repress ADA3-mediated transcriptional co-activation on nuclear receptors, whereas ANCO-1 stimulated p53-mediated transactivation. These data suggest that ADA3 is a newly identified target of the ANCO proteins, which may modulate co-activator function in a transcription-factor-specific manner.

scholarly journals Transcriptional Regulation of ZNF638 in Thermogenic Cells by the cAMP Response Element Binding Protein in Male Mice

2019 ◽  
Vol 3 (12) ◽  
pp. 2326-2340 ◽  
Author(s):  
Luce Perie ◽  
Narendra Verma ◽  
Lingyan Xu ◽  
Xinran Ma ◽  
Elisabetta Mueller
Keyword(s):  
Zinc Finger ◽  
Binding Protein ◽  
Regulatory Region ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Response Element ◽  
Element Binding Protein ◽  
Thermogenic Adipocytes

Abstract Zinc finger factors are implicated in a variety of cellular processes, including adipose tissue differentiation and thermogenesis. We have previously demonstrated that zinc finger protein 638 (ZNF638) is a transcriptional coactivator acting as an early regulator of adipogenesis in vitro. In this study, we show, to our knowledge for the first time, that, in vivo, ZNF638 abounds selectively in mature brown and subcutaneous fat tissues and in fully differentiated thermogenic adipocytes. Furthermore, gene expression studies revealed that ZNF638 is upregulated by cAMP modulators in vitro and by cold exposure and by pharmacological stimulation of β-adrenergic signaling in vivo. In silico analysis of the upstream regulatory region of the ZNF638 gene identified two putative cAMP response elements within 500 bp of the ZNF638 transcription start site. Detailed molecular analysis involving EMSA and chromatin immunoprecipitation assays demonstrated that cAMP response element binding protein (CREB) binds to these cAMP response element regions of the ZNF638 promoter, and functional studies revealed that CREB is necessary and sufficient to regulate the levels of ZNF638 transcripts. Taken together, these results demonstrate that ZNF638 is selectively expressed in mature thermogenic adipocytes and tissues and that its induction in response to classic stimuli that promote heat generation is mediated via CREB signaling, pointing to a possible novel role of ZNF638 in brown and beige fat tissues.

scholarly journals Aberrant expression of cAMP-response-element-binding protein (‘CREB’) induces apoptosis

1999 ◽  
Vol 343 (1) ◽  
pp. 249-255 ◽  
Author(s):  
Kumiko SAEKI ◽  
Akira YUO ◽  
Emiko SUZUKI ◽  
Yoshio YAZAKI ◽  
Fumimaro TAKAKU
Keyword(s):  
Cell Cycle ◽  
Expression Vector ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Dependent Manner ◽  
Transactivation Domain ◽  
Camp Response Element ◽  
Response Element ◽  
Element Binding Protein ◽  
Induction Of Apoptosis

We have reported previously that cAMP-response-element-binding protein (CREB) was phosphorylated in a cell-cycle-dependent manner, showing that it was phosphorylated at early S-phase at casein kinase II target sites. To assess the possible involvement of CREB in cell cycle progression, CREB expression vector was transiently transfected into various cells. Unexpectedly we found that transfection with CREB expression vector resulted in an abundance of dead cells. Morphological examination revealed that these cells had undergone apoptosis. The coincidence of CREB overexpression and apoptosis induction at the individual cell level was confirmed by a immunohistochemical study. To confirm that overexpression of CREB was the cause of apoptosis, a dominant-negative mutant of CREB, KCREB, was co-expressed with the wild type. The co-existence of KCREB effectively rescued CREB-mediated apoptosis in a dose-dependent manner, verifying that apoptosis was truly a specific effect of overexpressed CREB and not an artifact of the transfection procedure. Deletion analysis indicates that neither the Q1 transactivation domain, which functions in transcription, nor the kinase-inducible domain, in which a cluster of various kinase targets exists, is necessary; however, the Q2 transactivation domain is required for the induction of apoptosis. A more precise study indicates that the four-residue stretch Glu-Glu-Ala-Ala at the most C-terminal region of the Q2 domain is especially important for the induction of apoptosis. Thus overexpressed CREB induces apoptosis by transmitting certain signals from the C-terminal portion of the Q2 domain. Possible roles of cell-cycle-regulated phosphorylation and also an elevation of the intracellular cAMP level in CREB-induced apoptosis are suggested.

scholarly journals Cooperative regulation of endogenous cAMP-response element binding protein and CCAAT/enhancer-binding protein β in GH-stimulated c-fos expression

2007 ◽  
Vol 196 (1) ◽  
pp. 89-100 ◽  
Author(s):  
Tracy Xiao Cui ◽  
Roland Kwok ◽  
Jessica Schwartz
Keyword(s):  
Binding Protein ◽  
Mek Inhibitor ◽  
Camp Response Element Binding ◽  
Dominant Negative ◽  
Camp Response Element ◽  
Gh Treatment ◽  
Response Element ◽  
Element Binding Protein ◽  
Promoter Dna

GH activates the c-fos promoter by regulating multiple transcription factors. This study adds to our understanding of GH-regulated transcription by demonstrating that GH regulates the c-fos cAMP-response element (CRE) and its binding protein, CREB. Activation of the c-fos promoter by GH is impaired by expression of dominant-negative A-CREB. GH stimulates rapid and transient phosphorylation of CREB at Ser 133 (P-CREB), a critical site for transactivation by CREB, in 3T3-F442A preadipocytes. Mutation of this residue impairs GH-induced c-fos expression, suggesting that phosphorylation of CREB at Ser 133 contributes to GH-induced c-fos activation. The MEK inhibitor UO126 impaired the phosphorylation of CREB and that of C/EBPβ, suggesting that ERKs mediate the phosphorylation of both proteins. UO126, but not the protein kinase A inhibitor H89, blocked GH-induced c-fos mRNA expression. A combination of CREB and C/EBPβ enhanced c-fos promoter activation, and mutation of the CRE impaired the enhancement, as well as GH-stimulated c-fos activation. GH treatment increased the occupancy of both endogenous phospho-CREB and phospho-C/EBPβ on the c-fos promoter. The increases were impaired by UO126. The active P-CREB and P-C/EBPβ are induced by GH to occupy the same c-fos promoter DNA, suggesting that they may participate in a GH-regulated complex on c-fos. These findings suggest that coordinated phosphorylation of CREB and C/EBPβ in response to GH is mediated by ERK1/2, and that the phosphorylated proteins are part of a regulatory complex that occupies c-fos in vivo to regulate c-fos transcription cooperatively in response to GH.

A novel cyclic AMP response element-binding protein-1 (CREB-1) splice product may down-regulate CREB-1 activity

1995 ◽  
Vol 14 (2) ◽  
pp. 191-198 ◽  
Author(s):  
M J C Ellis ◽  
H C Hurst ◽  
S Goodbourn
Keyword(s):  
Cyclic Amp ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Transactivation Domain ◽  
Camp Response Element ◽  
Response Element ◽  
Element Binding Protein ◽  
Dependent Protein ◽  
Cyclic Amp Response Element ◽  
Splice Product

ABSTRACT In this report we identify novel spliced forms of cyclic AMP (cAMP) response element-binding protein-1 (CREB-1) mRNA. These forms contained an additional 17 nucleotide insert, which we refer to as the β exon, located between exons 4 and 7 of the Δ, and 5 and 7 of the α forms of CREB-1 transcript (nomenclature of Ruppert et al. 1992; EMBO Journal 11, 1503-1512). The inclusion of the β exon led to the generation of mRNAs in which the frame of CREB-1 sequences 3′ to the exon was shifted such that the encoded proteins terminate after the transactivation domain, but before the target serine for cAMP-dependent protein kinase. The β exon-containing CREB-1 mRNAs were more abundant in tissues that respond poorly to cAMP, suggesting that the generation of βCREB-1 mRNAs may contribute to the down-regulation of CREB-1 activity and cAMP responsiveness.

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