Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators

Deng, Wu; Zhu, Ying; Wu, Kenneth K.

doi:10.1182/blood-2003-09-3131

Cited by 133 publications

(128 citation statements)

References 34 publications

(42 reference statements)

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“…In addition, they possess intrinsic histone acetyltransferase (HAT) activity (Shikama et al, 1997). The functional roles of p300 in regulating COX-2 promoter activation have been demonstrated in previous studies of upregulation of COX-2 expression by inflammatory mediators such as phorbol 12-myristate 13-acetate, IL-1b or lipopolysaccharide (Deng et al, 2004). In the case of STAT6, we speculate that p300 may function as a result of its HAT activity and/or by bridging active interaction between STAT6 and general transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

et al. 2007

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Cyclooxygenase-2 (COX-2) is frequently overexpressed in human cancers and contributes to the malignant phenotype. Our data indicate unphosphorylated signal transducers and activators of transcription 6 (STAT6) may transcriptionally upregulate COX-2 expression and protect against apoptosis in NSCLC cells. In A427 and H2122, NSCLC cell lines that constitutively express COX-2, only unphosphorylated STAT6 was detectable by western blot, thus, all of the following STAT6-dependent effects are attributed to the unphosphorylated protein.In both cell lines, small-interfering RNA-mediated knockdown of STAT6 or stable expression of dominant-negative STAT6 decreased COX-2 expression. In contrast, transfection with a phosphorylation-deficient mutant STAT6 increased COX-2 levels. Immunofluorescent staining revealed the presence of STAT6 in H2122 nuclei, suggesting a direct role in gene regulation for the unphosphorylated protein. Consistent with this hypothesis, unphosphorylated STAT6 increased luciferase expression from a COX-2 promoter reporter construct. STAT6 coimmunoprecipitated with the transcriptional co-activator, p300, and chromatin immunoprecipitation assays demonstrated that these proteins bind a consensus STAT6 binding site located within the COX-2 promoter. STAT6 DNA-binding specificity was confirmed by electrophoretic mobility shift assay. As COX-2 over-expression has been clearly linked to apoptosis resistance and other hallmarks of malignancy, these findings suggest a novel role of unphosphorylated STAT6 in the pathogenesis of nonsmall cell lung cancer.

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Section: Discussionmentioning

confidence: 99%

Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

et al. 2007

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“…Results in this study demonstrated that HDAC inhibitor TSA upregulated the expression of miR-101b and miR-26b in LPS-treated macrophages from the aged mice, but not from the young mice, suggesting that HDAC suppresses the expression of miR-101b and miR-26b in the macrophages of aged mice. Deng et al (2004) reported that LPS could increase p300 HAT binding to COX-2 promoter and subsequently upregulate COX-2 protein levels. In the present study, we firstly observed that TSA strongly reduced the expression of COX-2 protein in response to LPS stimulation in aged mouse macrophages.…”

Section: Tsa Suppresses Cox-2 Protein Expression By Upregulation Of Mmentioning

confidence: 99%

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

Liú

Wang

et al. 2015

AGE

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Aging is the natural process of decline in physiological structure and function of various molecules, cells, tissues, and organs. Growing evidence indicates that increased immune genetic diversity and dysfunction of immune system cause aging-related pathophysiological process with the growth of age. In the present study, we observed that LPS-induced higher activation of cyclooxygenase (COX)-2 promoter is associated with the upregulated binding activity of nuclear factor kappa B (NF-κB) in peritoneal macrophages of aged mice than young ones. Additionally, COX-2 is a direct target of miR-101b and miR-26b in the macrophages. Significant upregulation of miR-101b and miR26b effectively prevented LPS-induced excessive expression of COX-2 in the young mice. Because these negative regulatory factors were unresponsive to LPS stimulation, the levels of COX-2 were markedly higher in the macrophages of aged mice. Further study showed that NF-κB activation contributed to the increase in the expression of miR-101b and miR-26b in the LPSstimulated macrophages of young mice, but not aged ones. Moreover, histone deacetylase (HDAC) inhibitor trichostatin A (TSA) upregulated expression of miR101b and miR-26b in the aged mouse macrophages only, but not the young cells. This demonstrated that HDAC suppressed the expression of miR-101b and miR-26b in the LPS-treated macrophages of aged mice and contributed to the aging process. TSA-induced increased expression of miR-101b and miR-26b could further suppress COX-2 expression. These findings provide novel evidence on the regulation of immune senescence and miR-101b and miR-26b, which might be promising targets in treating aged-related inflammatory diseases. Epigenetic regulation of the microRNAs (miRNAs) provides an important evidence for the treatment of innate inflammatory disease with HDAC inhibitors in elderly.

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“…Analysis of COX-2 Promoter Activity. A promoter region of human COX-2 gene (−891 to +9) was constructed into luciferase reporter vector pGL3 as previously described (38). A detailed procedure is provided in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…The negative control sequence was 5'-UUC UCCGA A CGU GUC ACG UTT-3'. Cells were transfected with siRNA duplexes using Lipofectamine 2000 (Invitrogen) as previously described (38). The procedure is described in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

Cheng¹,

Kuo²,

Yan³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.tumor suppression | tryptophan metabolism | inflammation control C yclooxygenase-2 (COX-2) is a rate-limiting enzyme in the production of diverse prostanoids with potent biological activities. It is involved in multiple physiological functions and triggers key pathological processes, such as tumorigenesis and inflammation (1, 2). COX-2 is constitutively overexpressed in a wide variety of human cancers and is enhanced by proinflammatory stimuli (3, 4). There is convincing evidence for a causal role of COX-2 in tumorigenesis. Inhibition of COX-2 activities was reported to control human colorectal cancer (5-8). COX-2 induces tumorigenesis by promoting important cellular functions including cell proliferation, migration, and resistance to apoptosis (9-11). The induced COX-2 expression by proinflammatory and mitogenic factors in normal cells is tightly controlled (12) whereas its overexpression in cancer cells is attributed to dysregulated transcription (13). The endogenous control mechanisms for COX-2 expression in normal cells and the mechanisms underlying the dysregulation in cancer cells are poorly understood. We previously identified in the conditioned medium of human fibroblasts small molecules (named cytoguardins) that suppress COX-2 expression induced by proinflammatory mediators (14). NMR analysis of a semipurified fraction revealed compounds with indole moieties (14). However, the exact chemical structures remain elusive. In this study, we elucidated the structure of cytoguardins by comparing the metabolomic profiles between normal and cancer cells. ResultsCytoguardins Inhibit Cancer Cell COX-2. To determine that fibroblast factors are capable of suppressing cancer cell COX-2 expression, we cocultured human Hs68 foreskin fibroblasts (HsFb) with A549 lung cancer cells in a Boyden chamber for 24 h. A549 cells were removed and treated with phorbol 12-myristate 13-acetate (PMA) for 4 h, and COX-2 proteins were analyzed. HsFb suppressed A549 ...

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Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators

Cited by 133 publications

References 34 publications

Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

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