Activating Transcription Factor 3 Activates p53 by Preventing E6-associated Protein from Binding to E6

Wang, Hongbo; Mo, Pingli; Ren, Shumei; Yan, Chunhong

doi:10.1074/jbc.m109.058669

Cited by 50 publications

(60 citation statements)

References 58 publications

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“…In contrast to the above results, ATF3 expression is decreased in human colorectal cancer (Bottone et al 2003), cervical cancer (Wang et al 2010), and glioma (Gargiulo et al 2013) compared with normal tissues, suggesting that ATF3 may act as a tumor suppressor. ATF3 activates p53 by preventing its ubiquitination and degradation in cervical cancer (Wang et al 2010).…”

Section: Neurodegenerativecontrasting

confidence: 49%

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Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

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Section: Neurodegenerativecontrasting

confidence: 49%

“…ATF3 activates p53 by preventing its ubiquitination and degradation in cervical cancer (Wang et al 2010). ATF3 also increases expression of MDM2 to facilitate MMP-2 degradation and subsequent inhibition of cell invasion in esophageal squamous cell carcinoma .…”

Section: Neurodegenerativementioning

confidence: 99%

Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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“…ATF3 contains 16 lysine residues, and 9 of them are clustered in the leucine zipper (Zip) domain that is required for binding to DNA and proteins (e.g. p53, E6) (3,4). Interestingly, MDM2 failed to catalyze ubiquitin modification of an ATF3 mutant (⌬102-139) lacking this domain (Fig.…”

Section: Atf3 Levels Correlate Inversely With Mdm2 Levels In Thementioning

confidence: 99%

“…These plasmids were transformed into BL21 strain, and expression of GST or GST fusion proteins was induced by isopropyl-␤-D-thiogalactopyranoside. GST pulldown assays were carried out as described previously (3,4). Immobilized GST fusion proteins were incubated with in vitro translated ATF3 or MDM2 at 4°C overnight, and bound proteins were detected by immunoblotting as described (22).…”

Section: P53mentioning

confidence: 99%

MDM2 Mediates Ubiquitination and Degradation of Activating Transcription Factor 3

Wang

et al. 2010

Journal of Biological Chemistry

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Activating transcription factor 3 (ATF3) is a common stress sensor, and its rapid induction by cellular stresses (e.g. DNA damage) is crucial for cells to mount appropriate responses (e.g. activating the tumor suppressor p53) and maintain homeostasis. Although emerging evidence suggests that dysregulation of ATF3 contributes to occurrences of human diseases including cancer, the mechanism(s) by which ATF3 expression is regulated is largely unknown. Here, we demonstrate that mouse double minute 2 (MDM2) is a bona fide E3 ubiquitin ligase for ATF3 and regulates ATF3 expression by promoting its degradation. MDM2 via its C-terminal RING finger can bind to the Basic region of ATF3 and mediate the addition of ubiquitin moieties to the ATF3 leucine zipper domain. As a consequence, ATF3, but not a mutant deficient in MDM2 binding (⌬80 -100), is degraded by MDM2-mediated proteolysis. Consistent with these results, ablation of MDM2 in cells not only increases basal ATF3 levels, but results in stabilization of ATF3 in late stages of DNA damage responses. Because ATF3 was recently identified as a p53 activator, these results suggest that MDM2 could inactivate p53 through an additional feedback mechanism involving ATF3. Therefore, we provide the first evidence demonstrating that ATF3 is regulated by a posttranslational mechanism. ATF32 is a member of the ATF/CREB family of transcription factors, and its expression is rapidly induced by a large variety of cellular stresses including DNA damage, wounds, and cellular injury (1). ATF3 can bind to DNA (via the ATF/CREB consensus sequence, 5Ј-TGACGTCA-3Ј) (1) and other proteins (e.g. Smad3, p53, and E6) (2-4), resulting in alterations in gene expression and cellular functions. Although consequences of stress-induced ATF3 expression are not well understood, recent evidence links ATF3 to several important pathways, including TGF␤ signaling (2), the Toll-like receptor 4 pathway (5), the eIF2 kinase-mediated endoplasmic reticulum stress response (6), as well as the p53 activation pathway (3), suggesting that dysregulation of ATF3 could contribute to occurrences of many human diseases including cancer. Indeed, although we previously showed that ATF3 deficiency promotes oncogenic transformation (3, 7), recent unbiased cDNA array studies have revealed that ATF3 expression is down-regulated in common human cancers (for a review of these data, see Ref. (8).Although induction of ATF3 expression is a common characteristic of stress responses (1), the mechanisms by which ATF3 expression is regulated during these processes remain largely unknown. It has been shown that ATF3 expression can be regulated by transcription factors such as ATF2, Smad3, and NF-B (2, 9, 10) and controlled by signaling mediated by p38 or JNK/SAPK (9, 11). Moreover, an atypical p53-binding site was identified in the ATF3 promoter (12). However, whether p53 regulates ATF3 expression still remains to be firmly validated, even though a marginal effect of p53 on ATF3 expression was reported in specific cells and in response...

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“…However, details of the function of this common stress response mediator remain largely unknown. Although ATF3 can bind to promoters and repress expression of some genes while activating expression of other genes (14), the findings that ATF3 can interact with other proteins (e.g., p53, Smad3, and E6) via its bZIP domain suggest that ATF3 may regulate cellular functions independent of its transcriptional activity (25,59,64). Indeed, the binding of ATF3 to the tumor suppressor p53 can activate the latter protein by protecting it from ubiquitin-mediated degradation (64).…”

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confidence: 99%

The Stress Response Mediator ATF3 Represses Androgen Signaling by Binding the Androgen Receptor

Wang

Jiang

Cui

et al. 2012

Molecular and Cellular Biology

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f Activating transcription factor 3 (ATF3) is a common mediator of cellular stress response signaling and is often aberrantly expressed in prostate cancer. We report here that ATF3 can directly bind the androgen receptor (AR) and consequently repress AR-mediated gene expression. The ATF3-AR interaction requires the leucine zipper domain of ATF3 that independently binds the DNA-binding and ligand-binding domains of AR, and the interaction prevents AR from binding to cisacting elements required for expression of androgen-dependent genes while inhibiting the AR N-and C-terminal interaction. The functional consequences of the loss of ATF3 expression include increased transcription of androgen-dependent genes in prostate cancer cells that correlates with increased ability to grow in low-androgen-containing medium and increased proliferative activity of the prostate epithelium in ATF3 knockout mice that is associated with prostatic hyperplasia. Our results thus demonstrate that ATF3 is a novel repressor of androgen signaling that can inhibit AR functions, allowing prostate cells to restore homeostasis and maintain integrity in the face of a broad spectrum of intrinsic and environmental insults.

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Activating Transcription Factor 3 Activates p53 by Preventing E6-associated Protein from Binding to E6

Cited by 50 publications

References 58 publications

Physiological/pathological ramifications of transcription factors in the unfolded protein response

Physiological/pathological ramifications of transcription factors in the unfolded protein response

MDM2 Mediates Ubiquitination and Degradation of Activating Transcription Factor 3

The Stress Response Mediator ATF3 Represses Androgen Signaling by Binding the Androgen Receptor

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