Interferon Regulatory Factor-2 Regulates Cell Growth through Its Acetylation

Masumi, Atsuko; Yamakawa, Yoshio; Fukazawa, Hidesuke; Ozato, Keiko; Komuro, Kaoru

doi:10.1074/jbc.m213037200

Cited by 48 publications

(59 citation statements)

References 56 publications

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“…Although previous studies have indicated that several IRF family members are acetylated and that acetylation inhibits their ability to bind DNA (21,22), our results do not support the notion that treatment of cells with TSA affects the ability of IRF9 to form an ISRE-binding complex with tyrosine-phosphorylated Stat1 and Stat2 (see Fig. 1).…”

Section: Resultscontrasting

confidence: 56%

Histone Deacetylase Activity Is Required to Recruit RNA Polymerase II to the Promoters of Selected Interferon-stimulated Early Response Genes

Sakamoto

Potla

Larner

2004

Journal of Biological Chemistry

120

119

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The biological actions of interferons (IFNs) 1 require the activation of immediate early genes, which are mediated by the Stat family of transcription factors (1). Type 1 interferons (IFN␣/␤) binding to their cell surface receptors initiate a set of events that leads to tyrosine phosphorylation of Stat1 and Stat2. Tyrosine-phosphorylated Stat1 and Stat2 heterodimerize through their Src homology 2 domains and translocate to the nucleus where they bind to interferon regulatory factor 9 (IRF9) to form the transcription complex ISGF3. ISGF3 binds to an interferon-stimulated response element (ISRE) that is present in many IFN␣/␤-stimulated genes. Alternatively, tyrosine-phosphorylated Stat1 can form homodimers and bind to a ␥ interferon activation sequence (GAS), an enhancer in the promoter of genes that do not require the participation of Stat2 or IRF9.Binding of ISGF3 to cellular genes containing ISREs is accompanied by changes in the chromatin structure of interferonstimulated genes (ISGs) (2). Cells incubated with IFN␣ show altered DNase I sensitivity surrounding the TATA box region as well as the ISRE of ISGs, suggesting that gene activation occurs as a result of chromatin remodeling (2). Consistent with this observation, both Stat1 and Stat2 have been shown to interact with the histone acetylases CBP/p300 and GCN5 resulting in increased association of the acetylated histone H3 with the promoter of the IFN␣/␤-stimulated gene ISG54 (3-6).From these observations one would predict that incubation of cells with HDAC inhibitors would increase IFN-activated gene expression, and this is indeed the case when one examines IFN␥-stimulated expression of the MHC-II (7). However, in contrast to IFN␥, interleukin-3-activated Stat5-dependent genes are inhibited in cells exposed to TSA (8), suggesting that in certain contexts HDAC activity may be required for Stat-dependent gene activation. Interestingly, other genes in which expression is activated by interleukin-3 in a Stat5-independent manner are unaffected by TSA. To examine the role of HDAC activity in the expression of genes regulated by Stat1 and Stat2, we have assayed for the expression of several RNAs in which genes are controlled by these transcription factors. To our surprise the actions of TSA on IFN␣/␤-stimulated gene expression were relatively selective. Whereas some IFN␣/␤-stimulated genes in which expression is regulated by an ISRE were strongly suppressed by TSA, others showed a more modest inhibition. Furthermore, genes in which activation required a GAS element, such as IRF-1, were not altered by TSA treatment. HDAC activity appears to be required to recruit RNA polymerase II (Pol II), but not Stat1 or Stat2, to the promoter of TSA-sensitive genes. The effects of TSA seem to be mediated either directly or indirectly by IRF9. Interestingly, if Pol II is already bound to the promoter and there is basal expression of the gene in the absence of IFN␣/␤ (i.e. IRF-1), then the suppressive actions of TSA are not observed. These data suggest a novel function for IRF9 ...

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Section: Resultscontrasting

confidence: 56%

Histone Deacetylase Activity Is Required to Recruit RNA Polymerase II to the Promoters of Selected Interferon-stimulated Early Response Genes

Sakamoto

Potla

Larner

2004

Journal of Biological Chemistry

120

119

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“…Acetylation of IRF-2 leads to inhibition of histone acetylation by p300 in vitro, suggesting a possible mechanism for transcriptional repression by IRF-2 in U937 cells (Masumi and Ozato, 2001). In contrast, we demonstrated that acetylation of IRF-2 regulates cell growth by activation of the H4 promoter (Masumi et al, 2003). In NIH3T3 cells, IRF-2 associates with endogenous p300 and becomes acetylated, binds to an ISRE site, and activates H4 promoter activity.…”

Section: Introductionmentioning

confidence: 66%

“…Interferon regulatory factor-2 recruits nucleolin in the presence of p300/CBP-associated factor Our previous report suggested that it is the involvement of cellular proteins associated with acetylated IRF-2, which results in its transcriptional regulation (Masumi et al, 2003). To identify those proteins that associate with acetylated IRF-2, we performed an M2-agarose pull-down assay using 293T cells transfected with flag-IRF-2 and flag-PCAF.…”

Section: Resultsmentioning

confidence: 99%

“…Exogenous p300/CBP-associated factor acetylates interferon regulatory factor-2 in 293T cells We have demonstrated previously that IRF-2 acts as a transcriptional activator upon acetylation (Masumi et al, 2003). To investigate IRF-2 acetylation by histone acetylases in vivo, flag-PCAF and flag-p300 were transfected into 293T cells with flag-IRF-2.…”

Section: Resultsmentioning

confidence: 99%

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Nucleolin is involved in interferon regulatory factor-2-dependent transcriptional activation

et al. 2006

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We have previously shown that Interferon regulatory factor‐2 (IRF‐2) is acetylated in a cell growth‐dependent manner, which enables it to contribute to the transcription of cell growth‐regulated promoters. To clarify the function of the acetylation of IRF‐2, we investigated the proteins that associate with acetylated IRF‐2. Transfection of p300/CBP‐associated factor (PCAF) enhanced acetylation of IRF‐2 in 293T cells. In cells transfected with both IRF‐2 and PCAF, IRF‐2 associated with endogenous nucleolin, in contrast, little association was observed when IRF‐2 was transfected with a PCAF HAT deletion mutant. In a pull‐down experiment using stable transfectants, acetylation defective mutant IRF‐2 (IRF‐2K75R) recruited nucleolin to much lower degree than that of wild type IRF‐2, suggesting that nucleolin preferentially associates with acetylated IRF‐2. Confocal analysis indicated that IRF‐2 colocalized with nucleolin in the perinucleolar region. Nucleolin in the presence of PCAF enhanced IRF‐2‐dependent H4 promoter activity in NIH3T3 cells. Affinity DNA binding analysis with H4 promoter DNA indicated that nucleolin associated with IRF‐2 in growing NIH3T3 cells, but not in growth‐arrested counterparts. We conclude that nucleolin is recruited to acetylated IRF‐2, contributing to gene regulation crucial for the control of cell growth.

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“…2 Indeed, several of the nuclear factors that are known to bind to the BLV LTR have been shown to interact with HATs (CREB/ATF, PU.1/Spi-B, USF2, the glucocorticoid receptor, IRF1, and IRF2) (14 -23) and/or with HDACs (rat CREB-1, PU.1, glucocorticoid receptor) (24 -26), and/or to be directly acetylated (rat CREB-1, human CREB-2, IRF2) (21,(27)(28)(29). Among these factors binding to the BLV LTR, the members of CREB/ATF family are of particular interest because they have been demonstrated to play a critical role in BLV gene expression and because they are known to interact with the transcriptional coactivators CBP/p300.…”

mentioning

confidence: 99%

Deacetylase Inhibitors and the Viral Transactivator TaxBLV Synergistically Activate Bovine Leukemia Virus Gene Expression via a cAMP-responsive Element- and cAMP-responsive Element-binding Protein-dependent Mechanism

Nguyên

Calomme

Wijmeersch

et al. 2004

Journal of Biological Chemistry

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Efficient bovine leukemia virus (BLV) transcription requires the virus-encoded transactivatorBovine leukemia virus (BLV) 1 is a B-lymphotropic retrovirus associated with enzootic bovine leukosis, a disease characterized by an increased number of B-lymphocytes and, in some cases, after a long latency period, by the subsequent development of B-cell leukemia or lymphosarcoma (1). BLV is closely related structurally and biologically to the human T-lymphotropic viruses HTLV-I and HTLV-II (1). Expression of BLV is regulated at the transcriptional level by the virus-encoded transactivator Tax BLV (2, 3). The molecular mechanism by which Tax BLV activates viral transcription is not fully understood. Transactivation by Tax BLV requires three 21-bp imperfect repeats located in the U3 region of the 5Ј long terminal repeat (LTR) (2, 4). These Tax BLV -responsive elements (called TxREs) contain a core octanucleotide sequence with similarity to the cAMP-responsive element (CRE) consensus (TGACGTCA) (5). The BLV CRE-like motifs located in the middle of each TxRE have been shown to serve as binding sites for three members of the basic leucine zipper (bZIP) family of cellular transcription factors: the CRE-binding protein (CREB) and the activating transcription factors-1 and Ϫ2 (ATF-1 and ATF-2) (4, 6). Because there is no evidence for direct binding of Tax BLV to DNA, it has been proposed that Tax BLV transactivation of the BLV promoter could be mediated, as reported for the HTLV-I system, through protein-protein interactions with CREB/ATF (4, 6, 7). The formation of this promoter-bound Tax BLV -CREB/ATF complex could then serve for the recruitment of the multifunctional cellular coactivators CBP (CREB-binding protein) and p300.There is now strong evidence that both transcriptional activation and silencing are mediated through the recruitment of enzymes that control protein acetylation: the histone deacetylases (HDACs) and the histone acetyltransferases (HATs). Acetylation of specific lysine residues within the amino-terminal tails of nucleosomal histones is generally linked to chroma-

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Interferon Regulatory Factor-2 Regulates Cell Growth through Its Acetylation

Cited by 48 publications

References 56 publications

Histone Deacetylase Activity Is Required to Recruit RNA Polymerase II to the Promoters of Selected Interferon-stimulated Early Response Genes

Histone Deacetylase Activity Is Required to Recruit RNA Polymerase II to the Promoters of Selected Interferon-stimulated Early Response Genes

Nucleolin is involved in interferon regulatory factor-2-dependent transcriptional activation

Deacetylase Inhibitors and the Viral Transactivator TaxBLV Synergistically Activate Bovine Leukemia Virus Gene Expression via a cAMP-responsive Element- and cAMP-responsive Element-binding Protein-dependent Mechanism

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