The Transcriptional Co-activator p/CIP (NCoA-3) Is Up-regulated by STAT6 and Serves as a Positive Regulator of Transcriptional Activation by STAT6

Arimura, Akinori; Peer, Maartje van; Schröder, Ann Sophie; Rothman, Paul B.

doi:10.1074/jbc.m404428200

Cited by 54 publications

(43 citation statements)

References 52 publications

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“…This is consistent with earlier data demonstrating different binding affinities of STAT6 for the ε (high affinity) and g1 (low affinity) promoter (27). Control PCRs diagnosing promoter regions of IgG2a (Ig2a) and of a proteasome gene, (Pr) (21,22), which lack STAT6 binding sites, did not generate signals (Fig. 4A, 4B).…”

Section: Efficient Stat6 Binding and Prevention Of Bcl6 Binding To I«supporting

confidence: 80%

Control of the STAT6–BCL6 Antagonism by SWAP-70 Determines IgE Production

Audzevich

Pearce

Breucha

et al. 2013

The Journal of Immunology

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Asthma and allergies are major health concerns in which Ig isotype E plays a pivotal role. Ag-bound IgE drives mast cells and basophils into exocytosis, thereby promoting allergic and potentially anaphylactic reactions. The importance of tightly regulated IgE production is underscored by severe immunological conditions in humans with elevated IgE levels. Cytokines direct IgH class-switching to a particular isotype by initiation of germline transcription (GLT) from isotype-specific intronic (I) promoters. The switch to IgE depends on IL-4, which stimulates GLT of the Iε promoter, but is specifically and strongly impaired in Swap-70−/− mice. Although early events in IL-4 signal transduction (i.e., activation of the JAK/STAT6 pathway) do not require SWAP-70, SWAP-70 deficiency results in impaired Iε GLT. The affinity of STAT6 to chromatin is reduced in absence of SWAP-70. Chromatin immunoprecipitation revealed that SWAP-70 binds to Iε and is required for association of STAT6 with Iε. BCL6, known to antagonize STAT6 particularly at Iε, is increased on Iε in absence of SWAP-70. Other promoters bound by BCL6 and STAT6 were found unaffected. We conclude that SWAP-70 controls IgE production through regulation of the antagonistic STAT6 and BCL6 occupancy of Iε. The identification of this mechanism opens new avenues to inhibit allergic reactions triggered by IgE.

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Section: Efficient Stat6 Binding and Prevention Of Bcl6 Binding To I«supporting

confidence: 80%

Control of the STAT6–BCL6 Antagonism by SWAP-70 Determines IgE Production

Audzevich

Pearce

Breucha

et al. 2013

The Journal of Immunology

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“…Although p160/SRC family coactivators NcoA-2 and p/CIP are closely related to SRC-1, and known to interact with CBP/p300, they do not directly interact with STAT6 (17). However, p/CIP mRNA and protein levels are up-regulated by IL-4, and p/CIP enhances IL-4 transcriptional responses through still an unknown mechanism that involves interaction with p300 (20). Thus, STAT6 employs several coactivator proteins through both direct and indirect interactions in recruiting CBP/p300 and basal transcriptional machinery to IL-4-responsive promoters.…”

Section: Discussionmentioning

confidence: 99%

“…SRC-1 functions as a coactivator for STAT6, as well as for STAT3 (18) and STAT5 (19). Also another member of the p160/ SRC family coactivators p/CIP (NcoA-3) indirectly interacts with STAT6 via p300 (20).…”

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confidence: 99%

The Transcriptional Co-activator Protein p100 Recruits Histone Acetyltransferase Activity to STAT6 and Mediates Interaction between the CREB-binding Protein and STAT6

Välineva

Yang

Palovuori

et al. 2005

Journal of Biological Chemistry

113

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STAT6 is a critical regulator of transcription for interleukin-4 (IL-4)-induced genes. Activation of gene expression involves recruitment of coactivator proteins that function as bridging factors connecting sequence-specific transcription factors to the basal transcription machinery, and as chromatin-modifying enzymes. Coactivator proteins CBP/p300 have been implicated in regulation of transcription in all STATs. CBP is also required for STAT6-mediated gene activation, but the underlying molecular mechanisms are still elusive. In this study we investigated the mechanisms by which STAT6 recruits CBP and chromatin-modifying activities to the promoter. Our results indicate that while STAT1-interacted directly with CBP, the interaction between STAT6 and CBP was found to be mediated through p100 protein, a coactivator protein that has previously been shown to stimulate the transcription of IL-4-induced genes. The staphylococcal nuclease-like (SN)-domains of p100 directly interacted with amino acids 1099 -1758 of CBP, while p100 did not associate with SRC-1, another coactivator of STAT6. p100 was found to recruit histone acetyltransferase (HAT) activity to STAT6 in vivo. Chromatin immunoprecipitation studies demonstrated that p100 increases the STAT6-p100-CBP ternary complex formation in the human Ig⑀ promoter. p100 also increased the amount of acetylated histone H4 at the Ig⑀ promoter, and siRNAs directed against p100 effectively inhibited Ig⑀ reporter gene expression. Our results suggest that p100 has an important role in the assembly of STAT6 transcriptosome, and that p100 stimulates IL-4-dependent transcription by mediating interaction between STAT6 and CBP and recruiting chromatin modifying activities to STAT6-responsive promoters.Signal transducer and activator of transcription (STAT) 1 family of transcription factors convert extracellular cytokine signals into diverse biological responses through modulation of gene transcription (1). Cytokines bind to their cognate receptors at the cell surface, which leads to the activation of receptor-associated JAK kinases, which in turn activate STATs by phosphorylating them at the conserved C-terminal tyrosine residue. The activated STATs undergo dimerization through a reciprocal SH2-phosphotyrosine interaction and translocate to the nucleus, where the STAT dimers bind to symmetrical TTC(N 2-4 )GAA DNA target elements. The specificity in cytokine signaling is conveyed by selective activation of different STATs by individual cytokine receptors, specific recognition of target DNA elements by various STATs, and through selective interaction and cooperation with other transcription factors and regulatory proteins.The family of STAT proteins consists of seven members that mediate highly specific functions in cytokine signaling. STAT6 is mediating interleukin-4 (IL-4)-and IL-13-induced gene responses (2). IL-4 is an important regulator of immune and anti-inflammatory responses. In T cells IL-4 mediates induction of Th2 differentiation, while inhibiting Th1 development, and in B ...

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“…There is evidence for a role played by NRF1 in regulating the expression of CXCR4 (19). NCOA3 and PRDM2 have been reported to be transcriptional co-activators (20,21), and Munier et al (22) have suggested that NCOA3 can interact with the HIV-1 LTR. STXBP2 is an interactor of SYNTAXIN 3, which acts on the membrane function and processes of the cell (23); however, it is unclear how knockdown of STXBP2 (directly or indirectly) affects the amount of reverse transcribed HIV-1 proviral DNA.…”

Section: Resultsmentioning

confidence: 99%

A Genome-wide Short Hairpin RNA Screening of Jurkat T-cells for Human Proteins Contributing to Productive HIV-1 Replication

Yeung

Houzet

Yedavalli

et al. 2009

Journal of Biological Chemistry

230

258

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Short interfering RNAs (siRNAs) have been used to inhibit HIV-1 replication. The durable inhibition of HIV-1 replication by RNA interference has been impeded, however, by a high mutation rate when viral sequences are targeted and by cytotoxicity when cellular genes are knocked down. To identify cellular proteins that contribute to HIV-1 replication that can be chronically silenced without significant cytotoxicity, we employed a shRNA library that targets 54,509 human transcripts. We used this library to select a comprehensive population of Jurkat T-cell clones, each expressing a single discrete shRNA. The Jurkat clones were then infected with HIV-1. Clones that survived viral infection represent moieties silenced for a human mRNA needed for virus replication, but whose chronic knockdown did not cause cytotoxicity. Overall, 252 individual Jurkat mRNAs were identified. Twenty-two of these mRNAs were secondarily verified for their contributions to HIV-1 replication. Five mRNAs, NRF1, STXBP2, NCOA3, PRDM2, and EXOSC5, were studied for their effect on steps of the HIV-1 life cycle. We discuss the similarities and differences between our shRNA findings for HIV-1 using a spreading infection assay in human Jurkat T-cells and results from other investigators who used siRNAbased screenings in HeLa or 293T cells.

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The Transcriptional Co-activator p/CIP (NCoA-3) Is Up-regulated by STAT6 and Serves as a Positive Regulator of Transcriptional Activation by STAT6

Cited by 54 publications

References 52 publications

Control of the STAT6–BCL6 Antagonism by SWAP-70 Determines IgE Production

Control of the STAT6–BCL6 Antagonism by SWAP-70 Determines IgE Production

The Transcriptional Co-activator Protein p100 Recruits Histone Acetyltransferase Activity to STAT6 and Mediates Interaction between the CREB-binding Protein and STAT6

A Genome-wide Short Hairpin RNA Screening of Jurkat T-cells for Human Proteins Contributing to Productive HIV-1 Replication

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