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PubMed2002

Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma.

The cAMP-response element-binding protein-binding protein (CBP) and p300 are common coactivators for several transcriptional factors. It has been reported that both CBP and p300 are significant for the activation of peroxisome proliferator-activated receptor gamma (PPARgamma), which is a crucial nuclear receptor in adipogenesis. However, it remains unclear whether CBP and/or p300 is physiologically essential to the activation of PPARgamma in adipocytes and adipocyte differentiation. In this study, we investigated the physiological significance of CBP/p300 in NIH3T3 cells transiently expressing PPARgamma and CBP and in 3T3-L1 preadipocytes stably expressing CBP- or p300-specific ribozymes. In PPARgamma-transfected NIH3T3 cells, induction of expression of PPARgamma target genes such as adipocyte fatty acid-binding protein (aP2) and lipoprotein lipase (LPL) by adding thiazolidinedione was enhanced, depending on the amount of a CBP expression plasmid transfected. Expression of aP2 and LPL genes, as well as glycerol-3-phosphate dehydrogenase activity and triacylglyceride accumulation after adipogenic induction, was largely suppressed in 3T3-L1 adipocytes expressing either the CBP- or p300-specific active ribozyme, but not in inactive ribozyme-expressing cells. These data suggest that both CBP and p300 are indispensable for the full activation of PPARgamma and adipocyte differentiation and that CBP and p300 do not mutually complement in the process.

3T3 Cells↗
PubMed2002

Functional analysis of hypoxia-inducible factor-1 alpha-mediated transactivation. Identification of amino acid residues critical for transcriptional activation and/or interaction with CREB-binding protein.

The hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a key regulator of adaptive responses to hypoxia. HIF-1 alpha has two independent transactivation domains (TADs). Whereas the N-terminal TAD (N-TAD) also constitutes a degradation box, the C-terminal TAD (C-TAD) functions in a strictly hypoxia-inducible fashion. Oxygen-dependent hydroxylation of an asparagine residue has recently been reported to regulate C-TAD function by disrupting the interaction with the CH1 domain of the p300/CBP coactivator at normoxia. Here we have performed alanine-scanning mutagenesis of a predicted alpha-helix within the C-TAD of mouse HIF-1 alpha to identify residues important for transactivation and interaction of the C-TAD with transcriptional coactivators. We observed that several hydrophobic residues, Ile(802), Leu(808), Leu(814), Leu(815), and Leu(818), were critical for transactivation and binding to the CH1 domain of CBP in hypoxic cells. Moreover, E812A/E813A and D819A mutations impaired hypoxia-dependent transactivation without disrupting binding to CH1. In the context of full-length HIF-1 alpha, mutation of the leucine residues conferred conformational changes to the protein and significantly reduced the transactivation function as well as functional interaction with the transcriptional coactivators CBP and SRC-1. These mutations also affected intranuclear redistribution of HIF-1 alpha in the presence of CBP, indicating that the integrity of the C-TAD is critical for intracellular localization of mouse HIF-1 alpha.

Amino Acid Motifs↗
PubMed2002

The transcriptional co-activators CREB-binding protein (CBP) and p300 play a critical role in cardiac hypertrophy that is dependent on their histone acetyltransferase activity.

The CBP and p300 proteins are transcriptional co-activators that are involved in a variety of transcriptional pathways in development and in response to specific signaling pathways. We have previously demonstrated that the ability of both these factors to stimulate transcription is greatly enhanced by treatment of cardiac cells with the hypertrophic agent phenylephrine (PE). Here, we show that inhibition of either CBP or p300 with antisense or dominant negative mutant constructs inhibits PE-induced hypertrophy as assayed by atrial naturetic protein production, cardiac cell protein:DNA ratio and cell size. Furthermore, we show that overexpression of CBP or p300 can induce hypertrophy and that this effect requires their histone acetyltransferase (HAT) activity. Moreover, we show that PE can directly enhance CBP HAT activity and that artificial enhancement of HAT activity is sufficient to induce hypertrophy. Hence, CBP and p300 play an essential role in hypertrophy induced by PE, and this effect is mediated via PE-induced enhancement of their HAT activity. This is the first time a role for these factors, and their HAT activity, in hypertrophy has been directly demonstrated.

Acetyltransferases↗
PubMed2003

The coactivator of transcription CREB-binding protein interacts preferentially with the glycosylated form of Stat5.

The signal transducer and activator of transcription (Stat) gene family comprises seven members with similarities in their domain structure and a common mode of activation. Members of this gene family mediate interferon induction of gene transcription and the response to a large number of growth factors and hormones. Extracellular ligand binding to transmembrane receptors causes the intracellular activation of associated tyrosine kinases, phosphorylation of Stat molecules, dimerization, and translocation to the nucleus. Prolactin-induced phosphorylation of Stat5 is a key event in the development and differentiation of mammary epithelial cells. In addition to the crucial phosphorylation at tyrosine 694, we have identified an O-linked N-acetylglucosamine (O-GlcNAc) as another secondary modification essential for the transcriptional induction by Stat5. This modification was only found on nuclear Stat5 after cytokine activation. Similar observations were made with Stat1, Stat3, and Stat6. Glycosylation of Stat5, however, does not seem to be a prerequisite for nuclear translocation. Mass spectrometric analysis revealed a glycosylated peptide in the N-terminal region of Stat5. Replacement of threonine 92 by an alanine residue (Stat5a-T92A) strongly reduced the prolactin induction of Stat5a glycosylation and abolished transactivation of a target gene promoter. Only the glycosylated form of Stat5 was able to bind the coactivator of transcription CBP, an essential interaction for Stat5-mediated gene transcription.

Acetylglucosamine↗
PubMed2004

Inhibition of lens fiber cell morphogenesis by expression of a mutant SV40 large T antigen that binds CREB-binding protein/p300 but not pRb.

Simian virus (SV) 40 large T antigen can both induce tumors and inhibit cellular differentiation. It is not clear whether these cellular changes are synonymous, sequential, or distinct responses to the protein. T antigen is known to bind to p53, to the retinoblastoma (Rb) family of tumor suppressor proteins, and to other cellular proteins such as p300 family members. To test whether SV40 large T antigen inhibits cellular differentiation in vivo in the absence of cell cycle induction, we generated transgenic mice that express in the lens a mutant version of the early region of SV40. This mutant, which we term E107KDelta, has a deletion that eliminates synthesis of small t antigen and a point mutation (E107K) that results in loss of the ability to bind to Rb family members. At embryonic day 15.5 (E15.5), the transgenic lenses show dramatic defects in lens fiber cell differentiation. The fiber cells become post-mitotic, but do not elongate properly. The cells show a dramatic reduction in expression of their beta- and gamma-crystallins. Because CBP and p300 are co-activators for crystallin gene expression, we assayed for interactions between E107KDelta and CBP/p300. Our studies demonstrate that cellular differentiation can be inhibited by SV40 large T antigen in the absence of pRb inactivation, and that interaction of large T antigen with CBP/p300 may be enhanced by a mutation that eliminates the binding to pRb.

Animals↗
PubMed2004

The co-activator CREB-binding protein participates in enhancer-dependent activities of bicoid.

Bicoid (Bcd) is a transcriptional activator required for early embryonic patterning in Drosophila. Despite extensive studies, it currently remains unclear how Bcd activates transcription and what proteins participate in its activation process. In this report, we describe experiments to analyze the role of the Drosophila co-activator dCBP in Bcd-mediated activation. In Drosophila S2 cells, the Bcd activity is increased by the co-transfection of plasmids expressing dCBP and reduced by double-stranded RNA-mediated interference against dCBP. We further show that Bcd and dCBP can interact with each other and that Bcd-interacting domains of dCBP can cause dominant negative effects on Bcd activity in S2 cells. Our comparison of two Bcd-responsive enhancers, hunchback (hb) and knirps (kni), reveals a differential role of dCBP in facilitating Bcd activation. A dCBP mutant defective in its histone acetyltransferase activity exhibits a reduced, but not abolished, co-activator function for Bcd. Our chromatin immunoprecipitation experiments show that dCBP can increase not only the occupancy of Bcd itself at the enhancers but also the recruitment of general transcription factors to the promoter. Together, these experiments suggest that dCBP is an enhancer-dependent co-activator of Bcd, facilitating its activation through multiple mechanisms.

Acetyltransferases↗
PubMed2006

Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3'-end processing.

Trichostatin A (TSA), a specific inhibitor of histone deacetylases (HDACs), induces acetylation of various non-histone proteins such as p53 and alpha-tubulin. We purified several acetylated proteins by the affinity to an anti-acetylated lysine (AcLys) antibody from cells treated with TSA and identified them by mass spectrometry. Here we report on acetylation of CFIm25, a component of mammalian cleavage factor Im (CF Im), and poly(A) polymerase (PAP), a polyadenylating enzyme for the pre-mRNA 3'-end. The residues acetylated in these proteins were mapped onto the regions required for interaction with each other. Whereas CBP acetylated these proteins, HDAC1, HDAC3, HDAC10, SIRT1, and SIRT2 were involved in in vivo deacetylation. Acetylation of the CFIm25 occurred depending on the cleavage factor complex formation. Importantly, the interaction between PAP and CF Im complex was decreased by acetylation. We also demonstrated that acetylation of PAP inhibited the nuclear localization of PAP by inhibiting the binding to the importin alpha/beta complex. These results suggest that CBP and HDACs regulate the 3'-end processing machinery and modulate the localization of PAP through the acetylation and deacetylation cycle.

3' Untranslated Regions↗
PubMed2005

Transcriptional regulation of cyclooxygenase-2 in response to proteasome inhibitors involves reactive oxygen species-mediated signaling pathway and recruitment of CCAAT/enhancer-binding protein delta and CREB-binding protein.

Inhibition of ubiquitin-proteasome pathway has been shown to be a promising strategy for the treatment of inflammation and cancer. Here, we show that proteasome inhibitors MG132, PSI-1, and lactacystin induce COX-2 expression via enhancing gene transcription rather than preventing protein degradation in the human alveolar NCI-H292 and A549, and gastric AGS epithelial cells. NF-IL6 and CRE, but not NF-kappaB elements on the COX-2 promoter were involved in the gene transcription event. The binding of CCAAT/enhancer binding protein (C/EBP)beta and C/EBPdelta to the CRE and NF-IL6 elements, as well as the recruitment of CBP and the enhancement of histone H3 and H4 acetylation on the COX-2 promoter was enhanced by MG132. However, it did not affect the total protein levels of C/EBPbeta and C/EBPdelta. MG132-induced DNA-binding activity of C/EBPdelta, but not C/EBPbeta was regulated by p38, PI3K, Src, and protein kinase C. Small interfering RNA of C/EBPdelta suppressed COX-2 expression, further strengthening the role of C/EBPdelta in COX-2 gene transcription. In addition, the generation of intracellular reactive oxygen species (ROS) in response to MG132 contributed to the activation of MAPKs and Akt. These findings reveal that the induction of COX-2 transcription induced by proteasome inhibitors requires ROS-dependent protein kinases activation and the subsequent recruitments of C/EBPdelta and CBP.

CCAAT-Enhancer-Binding Protein-delta↗
PubMed1997

The transcriptional integrator CREB-binding protein mediates positive cross talk between nuclear hormone receptors and the hematopoietic bZip protein p45/NF-E2.

Thyroid hormone (T3) and retinoic acid (RA) play important roles in erythropoiesis. We found that the hematopoietic cell-specific bZip protein p45/NF-E2 interacts with T3 receptor (TR) and RA receptor (RAR) but not retinoid X receptor. The interaction is between the DNA-binding domain of the nuclear receptor and the leucine zipper region of p45/NF-E2 but is markedly enhanced by cognate ligand. Remarkably, ligand-dependent transactivation by TR and RAR is markedly potentiated by p45/NF-E2. This effect of p45/NF-E2 is prevented by maf-like protein p18, which functions positively as a heterodimer with p45/NF-E2 on DNA. Potentiation of hormone action by p45/NF-E2 requires its activation domain, which interacts strongly with the multifaceted coactivator cyclic AMP response element protein-binding protein (CBP). The region of CBP which interacts with p45/NF-E2 is the same interaction domain that mediates inhibition of hormone-stimulated transcription by AP1 transcription factors. Overexpression of the bZip interaction domain of CBP specifically abolishes the positive cross talk between TR and p45/NF-E2. Thus, positive cross talk between p45/NF-E2 and nuclear hormone receptors requires direct protein-protein interactions between these factors and with CBP, whose integration of positive signals from two transactivation domains provides a novel mechanism for potentiation of hormone action in hematopoietic cells.

Animals↗
PubMedDate not supplied

Molecular plasticity in the rat auditory brainstem: modulation of expression and distribution of phosphoserine, phospho-CREB and TrkB after noise trauma.

We induced acoustic trauma by applying click stimuli of 130 dB (SPL) for 30 min to one ear of adult rats. This treatment resulted in an instant and permanent threshold shift of 96 dB in the affected ear. A massive reduction of cochlear nerve fibers in the ventral cochlear nucleus (VCN) was demonstrated by tracing them from the cochlea of rats that survived acoustic overstimulation for 1 year or longer. In the auditory brainstem, we observed a deprivation-dependent appearance of fibers positive for tyrosine receptor kinase B in the ipsilateral VCN between day 3 and day 21 after trauma and an increase in phosphoserine immunostaining in the neuropil of the ipsilateral VCN and in neurons of the contralateral lateral superior olive during the first 30 days after trauma. Immunoreactivity for the cAMP response element binding protein in its phosphorylated form was transiently depressed in the ipsilateral inferior colliculus immediately after trauma and was elevated as late as 7 months after trauma in the ipsilateral VCN. Apparently, a unilateral acoustic overstimulation entails specific regulations of the activity of plasticity-associated molecules through phosphorylation and includes changes to neurotrophin signaling between neurons of the auditory brainstem.

Animals↗
PubMed2004

Estrogen receptor-alpha interaction with the CREB binding protein coactivator is regulated by the cellular environment.

The p160 coactivators, steroid receptor coactivator-1 (SRC-1), transcriptional intermediary factor-2 (TIF2) and receptor-associated coactivator-3 (RAC3), as well as the coactivator/integrator CBP, mediate estrogen receptor-alpha (ERalpha)-dependent gene expression. Although these coactivators are widely expressed, ERalpha transcriptional activity is cell-type dependent. In this study, we investigated ERalpha interaction with p160 coactivators and CBP in HeLa and HepG2 cell lines. Basal and estradiol (E2)-dependent interactions between the ERalpha ligand-binding domain (LBD) and SRC-1, TIF2 or RAC3 were observed in HeLa and HepG2 cells. The extents of hormone-dependent interactions were similar and interactions between each of the p160 coactivators and the ERalpha LBD were not enhanced by 4-hydroxytamoxifen in either cell type. In contrast to the situation for p160 coactivators, E2-dependent interaction of the ERalpha LBD with CBP or p300 was detected in HeLa but not HepG2 cells by mammalian two-hybrid and coimmunoprecipitation assays, indicating that the cellular environment modulates ERalpha-CBP/p300 interaction. Furthermore, interactions between CBP and p160 coactivators are much more robust in HeLa than HepG2 cells suggesting that poor CBP-p160 interactions are insufficient to support ERalpha-CBP-p160 ternary complexes important for nuclear receptor-CBP interactions. Alterations in p160 coactivators or CBP expression between these two cell types did not account for differences in ERalpha-p160-CBP interactions. Taken together, these data revealed the influence of cellular environment on ERalpha-CBP/p300 interactions, as well as CBP-p160 coactivator binding, and suggest that these differences may contribute to the cell specificity of ERalpha-dependent gene expression.

CREB-Binding Protein↗
PubMed2000

MHC class II transactivator inhibits IL-4 gene transcription by competing with NF-AT to bind the coactivator CREB binding protein (CBP)/p300.

The MHC class II transactivator (CIITA) activates the expression of multiple genes involved in Ag presentation, but inhibits Th2-type cytokine production, including IL-4, during Th1 cell differentiation. Th1 cells derived from CIITA-deficient mice produce both Th1- and Th2-type cytokines, and the introduction of CIITA to Th2 cells down-regulates Th2-type cytokine gene transcription. Here we show that the IL-4 promoter is regulated by multiple protein-protein interactions among CIITA, NF-AT, and coactivator CBP/p300. The introduction of CBP/p300 and NF-AT enhances the IL-4 promoter activity, and this activation was repressed by CIITA. Furthermore, our data show that CIITA competes with NF-AT to bind CBP/p300 and that this competition dramatically influences transcriptional activation of the IL-4 promoter. We identified two domains of CIITA that interact with two distinct domains of CBP/p300 that are also recognized by NF-AT. CIITA mutants that retain the ability to interact with CBP/p300 are sufficient to inhibit NF-AT-mediated IL-4 gene expression.

Binding, Competitive↗
PubMed2006

Functional interaction of CREB binding protein (CBP) with nuclear transport proteins and modulation by HDAC inhibitors.

Nuclear transport proteins such as CSE1, NUP93 and Importin-alpha have recently been shown to be chromatin-associated proteins in yeast, which have unexpected functions in gene regulation. Here we report interactions between the mammalian histone acetyltransferase CBP with nuclear transport proteins CAS (a CSE1 homologue) and Importin-alpha (Impalpha) and NUP93. CAS was found to bind the SRC1 interaction domain (SID) of CBP via a leucine-rich motif in the N-terminus of the protein, that is conserved in other SID-binding proteins. Coimmunoprecipitation experiments also revealed that CBP and Impalpha proteins form a complex. As Impalpha is a known acetylation target of CBP/p300, and is recycled to the cytoplasm via the exportin CAS, we investigated whether HDAC inhibitors would alter the subcellular localization of these proteins. Treatment of COS-1 cells with the HDAC inhibitors trichostatin A or sodium butyrate resulted in sequestration of Impalpha in the nuclear envelope, accumulation of CAS in nuclear aggregates, and an increased number of CBP-containing PML bodies per cell. In addition, HDACi treatment appeared to enhance the association of Impalpha and CBP in coimmunoprecipitation experiments. Our results provide evidence for novel functional interactions between the chromatin modification enzyme CBP and nuclear transport proteins in mammalian cells.

Active Transport, Cell Nucleus↗
PubMed1999

Recruitment of CREB-binding protein by PU.1, IFN-regulatory factor-1, and the IFN consensus sequence-binding protein is necessary for IFN-gamma-induced p67phox and gp91phox expression.

Activation of the phagocyte respiratory burst oxidase requires interaction between the oxidase components p47phox, p67phox, p22phox, and gp91phox. IFN-gamma induces transcription of the genes encoding p67phox (the NCF2 gene) and gp91phox (the CYBB gene) during monocyte differentiation, and also in mature monocytes. In these studies, we identify an NCF2 cis element, necessary for IFN-gamma-induced p67phox expression, and determine that this element is activated by cooperation between the transcription factors PU.1, IFN regulatory factor 1 (IRF1), and the IFN consensus-binding protein (ICSBP). Previously, we identified a CYBB cis element, necessary for IFN-gamma-induced gp91phox expression, and also activated by this transcription factor combination. In these investigations, we determine that recruitment of a coactivator protein, CBP (the CREBbinding protein), to the CYBB or NCF2 promoter is the molecular mechanism of transcriptional activation by PU.1, IRF1, and ICSBP. Also, we determine that the multiprotein interaction of CBP with PU. 1, IRF1, and ICSBP requires either the CYBB- or NCF2--binding site. Because IFN-gamma induces simultaneous expression of p67phox and gp91phox, these investigations identify a molecular event that coordinates oxidase gene transcription during the inflammatory response. Also, these investigations identify CBP recruitment by cooperation between PU.1, IRF1, and ICSBP as a novel molecular mechanism for IFN-gamma-induced activation of myeloid genes that are involved in the system of host defense.

Base Sequence↗