A Splice Variant of Stress Response Gene ATF3 Counteracts NF-κB-dependent Anti-apoptosis through Inhibiting Recruitment of CREB-binding Protein/p300 Coactivator

Hua, Bayin; Tamamori‐Adachi, Mimi; Luo, Yuan; Tamura, Kiyoshi; Morioka, M.; Fukuda, Mizue; Tanaka, Yujiro; Kitajima, Shigetaka

doi:10.1074/jbc.m508471200

Cited by 49 publications

(36 citation statements)

References 48 publications

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“…Previous studies have shown that ER recruitment to the CRH promoter is accompanied by an increase in H3 acetylation, as well as CBP recruitment (34). CBP has also been shown to be important for NF-B action on the BIRC3 gene (25). In MCF-7 breast cancer cells, CBP appears to be present constitutively at the BIRC3 promoter.…”

Section: Discussionmentioning

confidence: 97%

CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter

Pradhan

Baumgarten

Bembinster

et al. 2012

Molecular and Cellular Biology

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Estrogen receptor (ER) and NF-B are transcription factors with profound effects on breast cancer cell proliferation and survival. While many studies demonstrate that ER and NF-B can repress each other, we previously identified a gene signature that is synergistically upregulated by these two factors in more aggressive luminal B breast tumors. Herein, we examine a novel mechanism of cross talk between ER and NF-B that results in the upregulation of the antiapoptotic gene BIRC3 (also known as cIAP2). We demonstrate that NF-B, acting through two response elements, is required for ER recruitment to an adjacent estrogen response element (ERE) in the BIRC3 promoter. This effect is accompanied by a major increase in NF-B-dependent histone acetylation around the ERE. Interestingly, CBP, a histone acetyltransferase previously implicated in repressive interactions between ER and NF-B, plays a permissive role by promoting histone acetylation and ER recruitment, as well as enhanced expression of BIRC3. These findings suggest a new gene regulatory mechanism by which inflammation and NF-B activation can influence ER recruitment to inherently inactive ER binding sites. This fine-tuning mechanism may explain how two factors that generally repress each other's activity may work together on certain genes to promote breast cancer cell survival and tumor progression. T he estrogen receptor (ER) is expressed in approximately 75%of breast cancers, and women with such tumors are generally treated with endocrine therapies, such as tamoxifen or aromatase inhibitors. However, not all ER-positive tumors respond to these therapies. Through gene expression profiling studies, ER-positive tumors have been delineated into two intrinsic subtypes, luminal A and luminal B (48, 49). Women with the luminal A subtype of breast tumors respond well to therapy and have a good prognosis, whereas the outcome is poor for women with the luminal B subtype of tumors, nearly as poor as that seen in the case of ERnegative tumors. Our lab recently identified a gene signature synergistically upregulated by cross talk between ER and NF-B that is highly associated with luminal B but not luminal A-type tumors (16). This signature is enriched for cell survival genes, including the cellular inhibitor of apoptosis gene, cIAP2, which is also known as BIRC3. We have previously shown that BIRC3 is upregulated by estradiol (E2) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-␣) in a number of ER-positive but not ER-negative cell lines. Using chemical inhibitors and a small interfering RNA (siRNA) approach, our lab has further demonstrated that BIRC3 plays an important role in promoting estrogendependent breast cancer cell survival and protecting against TNF-␣-induced cell death (51). Understanding the mechanism by which BIRC3 is upregulated by cross talk between ER and NF-B is therefore of clinical relevance.The ER subtypes, ER␣ and ER␤, are ligand-dependent transcription factors that interact with DNA and control transcription of ER target genes in resp...

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Section: Discussionmentioning

confidence: 97%

CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter

Pradhan

Baumgarten

Bembinster

et al. 2012

Molecular and Cellular Biology

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“…The observation that M2 induces viral gene expression in ganglia harboring latent virus and maintained in medium containing NGF plus EGF suggests that M2 acts as a dominant negative factor, possibly by interacting with a partner other than ATF3. As noted in the introductory section, ATF3 can form heterodimers with other members of ATF/CREB proteins (36,37). M2 contains the ZIP domain required for the formation of homodimers or heterodimers, but it does not interact with WT ATF3.…”

Section: Discussionmentioning

confidence: 99%

Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia

Shu

Zhou

et al. 2015

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

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A key property of herpes simplex viruses (HSVs) is their ability to establish latent infection in sensory or autonomic ganglia and to reactivate on physical, hormonal, or emotional stress. In latently infected ganglia, HSVs express a long noncoding RNA, a latency-associated transcript (LAT), which plays a key role in maintaining latently infected neurons, but not viral proteins. To investigate the events leading to reactivation, we examined the use of ganglionic organ cultures that enable rapid reactivation in medium containing antibody to nerve growth factor (NGF) or delayed reactivation in medium containing NGF and epidermal growth factor (EGF). Here we report the discovery that activating transcription factor 3 (ATF3), a stress response protein, profoundly affects the interaction of HSV with its host. Specifically, (i) ATF3 is induced by stress, such as inhibition of protein synthesis or infection; (ii) in infected cells, ATF3 enhances the accumulation of LAT by acting on the response elements in the promoter of the LAT precursor RNA; (iii) ATF3 is induced nearly 100-fold in ganglionic organ cultures; and (iv) ATF3 plays a key role in the maintenance of the latent state, inasmuch as expression of ATF3 bereft of the C-terminal activation domain acts as a dominant negative factor, inducing HSV gene expression in ganglionic organ cultures harboring latent virus and incubated in medium containing NGF and EGF. Thus, ATF3 is a component of a cluster of cellular proteins that together with LAT maintain the integrity of the neurons harboring latent virus.

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“…Recently, it has been described that a spliced variant of ATF-3 but not of the full-length ATF-3 sensitizes cells to apoptosis, partly by suppressing expression of NF-B-dependent antiapoptotic genes (47). Thus, we next defined by EMSA the NF-B activation in ATF3…”

Section: Atf-3 Is Involved In Pkr-inducedmentioning

confidence: 99%

Human Gene Profiling in Response to the Active Protein Kinase, Interferon-induced Serine/threonine Protein Kinase (PKR), in Infected Cells

Guerra¹,

López-Fernández

García³

et al. 2006

Journal of Biological Chemistry

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The interferon-induced serine/threonine protein kinase (PKR) has an essential role in cell survival and cell death after viral infection and under stress conditions, but the host genes involved in these processes are not well defined. We used human cDNA microarrays to identify, in infected cells, genes differentially expressed after PKR expression and analyzed the requirement of catalytic activity of the enzyme. To express PKR, we used vaccinia virus (VV) recombinants producing wild type PKR (VV-PKR) and the catalytically inactive mutant K296R (VV-PKR-K296R). Most regulated genes were classified according to biological function, including apoptosis, stress, defense, and immune response. Transcriptional changes detected by microarray analysis were confirmed for selected genes by quantitative real time reverse transcription PCR. A total of 111 genes were regulated specifically by PKR catalytic activity. Of these, 97 were up-regulated, and 14 were downregulated. The ATF-3 transcription factor, involved in stress-induced ␤-cell apoptosis, was up-regulated. Activation of endogenous PKR with a VV mutant lacking the viral protein E3L (VV⌬E3L), a PKR inhibitor, triggered an increase in ATF-3 expression that was not observed in PKR ؊/؊ cells. Using null cells for ATF-3 and for the p65 subunit of NF-B, we showed that induction of apoptosis by PKR at late times of infection was dependent on ATF-3 expression and regulated by NF-B activation. Here, we identified human genes selectively induced by expression of active PKR in infected cells and linked ATF-3 to a novel mechanism used by PKR to induce apoptosis.The double-stranded RNA (dsRNA) 4 -dependent protein kinase (PKR) is a key mediator in the antiviral effects of interferon (IFN) and a dynamic participant in apoptosis induced by various stimuli (1) (reviewed in Ref.2). PKR controls cell processes, such as growth (3) differentiation (4), apoptosis (5, 6), stress response (7), anti-tumor activity (8, 9), and antiviral functions (10, 11). After PKR activation, the initiation of protein synthesis is inhibited by phosphorylation of the ␣ subunit of the eukaryotic initiation factor 2 (eIF-2␣) by PKR (12). This kinase regulates the activation of several transcription factors involved in virus-induced apoptosis (13), including p53 (14), IRF-1 (15), and IRF-3, and activation of c-Jun (16). By regulating the expression of genes involved in cell proliferation, NF-B induction is important in mediating PKR function (16). NF-B activation by PKR also triggers production of 17), an essential component in PKR functionality.The genes involved in PKR-induced apoptosis in infected human cells have not been defined. We previously described an isopropyl-␤-D-thiogalactopyranoside-inducible VV system in which PKR expression triggers apoptosis (5) (for a review, see Ref. 18). When PKR was expressed, the antiviral action against VV and vesicular stomatitis virus provoked a translational block by phosphorylation of eIF-2␣ and triggered NF-B activation through the IB kinase complex (5,10,11,19,20)....

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A Splice Variant of Stress Response Gene ATF3 Counteracts NF-κB-dependent Anti-apoptosis through Inhibiting Recruitment of CREB-binding Protein/p300 Coactivator

Cited by 49 publications

References 48 publications

CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter

CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter

Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia

Human Gene Profiling in Response to the Active Protein Kinase, Interferon-induced Serine/threonine Protein Kinase (PKR), in Infected Cells

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