The Stress-responsive Gene ATF3 Mediates Dichotomous UV Responses by Regulating the Tip60 and p53 Proteins

Cui, Hongmei; Li, Xingyao; Han, Chunhua; Wang, Qi En; Wang, Hongbo; Ding, Han‐Fei; Zhang, Junran; Yan, Chunhong

doi:10.1074/jbc.m115.713099

Cited by 25 publications

(27 citation statements)

References 41 publications

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“…ATF3 is a well-studied regulator of p53dependent transcription through control of p53 stability and co-factor recruitment (26,56,57). Previous reports clearly demonstrate that ATF3 can directly alter p53 stability and modulate p53 activity through interactions with histone modifying enzymes (56,57,65). Our work uniquely identifies a direct role for ATF3 DNA binding within a p53-bound CRE and demonstrates a positive effect on p53-dependent transcriptional activity.…”

Section: The Requirement For Other Transcription Factors Co-regulatinsupporting

confidence: 60%

“…6C). We therefore focused on ATF3 because of its previous association as a positive regulator of p53 activity and its well-known role as a modulator of the inflammatory response (26,(56)(57)(58), of which GDF15 is a central regulator (53). Using a luciferase reporter approach, we assessed the activity of the GDF15 E1 enhancer in wild-type, p53-deficient, or ATF3-deficient HCT116 cells.…”

Section: P53-dependent Transcription Of Gdf15 Requires Regulatory Facmentioning

confidence: 99%

“…6D-E). ATF3 is a well-studied regulator of p53dependent transcription through control of p53 stability and co-factor recruitment (26,56,57). Previous reports clearly demonstrate that ATF3 can directly alter p53 stability and modulate p53 activity through interactions with histone modifying enzymes (56,57,65).…”

Section: The Requirement For Other Transcription Factors Co-regulatinmentioning

confidence: 99%

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Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

Catizone

Uzunbas

Celadova

et al. 2019

Preprint

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The master tumor suppressor p53 controls transcription of a wide-ranging gene network involved in apoptosis, cell cycle arrest, DNA damage repair, and senescence. Recent studies revealed pervasive binding of p53 to cis-regulatory elements (CRE), which are non-coding segments of DNA that spatially and temporally control transcription through the combinatorial binding of local transcription factors (TFs). Although the role of p53 as a strong trans-activator of gene expression is well known, the coregulatory factors and local sequences acting at p53-bound CREs are comparatively understudied. We designed and executed a massively parallel reporter assay (MPRA) to investigate the effect of transcription factor binding motifs and local sequence context on p53-bound CRE activity. Our data indicate that p53-bound CREs are both positively and negatively affected by alterations in local sequence context and changes to co-regulatory TF motifs. We identified a SP1/KLF family motif located in an intronic p53 CRE that is required for the endogenous expression of the p53-dependent gene CCNG1. We also identified ATF3 as a factor that co-regulates the expression of the p53-dependent gene GDF15 through binding with p53 in an upstream CRE. Loss of either p53 or ATF3 severely reduces CRE activity and alters endogenous GDF15 mRNA levels in the cell. Our data suggests that p53 has the flexibility to cooperate with a variety of transcription factors in order to regulate CRE activity. By utilizing different sets of co-factors across CREs, we hypothesize that p53 activity is guarded against loss of any one regulatory partner allowing for dynamic and redundant control of p53mediated transcription.Recent evidence suggests that sequence variation within cis-regulatory elements (CREs) can influence p53 binding, transcriptional activity, and tumor suppressor function (5-7) . The critical nature of the core p53 response element (p53RE) on p53 binding and CRE activity is well understood (8-10), but the influence of local sequence variation and the role of transcription factor motifs outside of the p53RE on p53 activity remains an open and vital question.Cis-regulatory elements, such as promoters and enhancers, govern gene expression through temporal, spatial, and quantitative control of transcription (11,12). While multiple models for CRE function have been proposed, the majority involve cooperative binding and activity of multiple transcription factors and cofactors acting locally to fine-tune gene expression (11)(12)(13). The presence and availability of transcription factors, repressors, and other cofactors vary across cell states such as development, stress, disease, and cell type (14-17). This variability provides a mechanism for differential CRE activity and downstream gene expression. Loss of transcription factor binding within a CRE, through variation in DNA sequence or through changes in trans-factor availability, can strongly influence CRE activity and gene expression (11,12,18), with direct implications in numerous developmental and d...

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Section: The Requirement For Other Transcription Factors Co-regulatinsupporting

confidence: 60%

Section: P53-dependent Transcription Of Gdf15 Requires Regulatory Facmentioning

confidence: 99%

Section: The Requirement For Other Transcription Factors Co-regulatinmentioning

confidence: 99%

See 1 more Smart Citation

Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

Catizone

Uzunbas

Celadova

et al. 2019

Preprint

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“…H1299 and U2OS cells were obtained from ATCC, and cultured in RPMI 1640 and DMEM supplemented with 10% FBS, respectively. ATF3-knockout U2OS cells were generated by CRISPR/Cas9 as previously described [27]. To reconstitute with wild-type ATF3 and ATF3 mutants, ATF3-KO cells were transfected with FLAG-ATF3wt, FLAG-K107R, FLAG-K108R, or FLAG-R88G using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instruction.…”

Section: Cell Culture and Transfectionsmentioning

confidence: 99%

“…The result that ATF3wt transactivated rather than repressed the synthetic ATF/Cre reporter (3×ATF/Cre-Luc) was somewhat unexpected [32], but ATF3 binding to DNA can result in either activation or repression of transcription in a context-dependent manner [13]. To determine effects of the ATF3 mutants on p53 activation in vivo, we knocked out the endogenous ATF3 gene by CRISPR/Cas9 from U2OS cells [27] and reconstituted the cells with ATF3wt, K107R, or K108R. The derived cell lines expressed ATF3wt, K107R, or K108R at a comparable level (Fig.…”

Section: Atf3 Mutants Devoid Of Ubiquitination Have a Defect In Activmentioning

confidence: 99%

Competitive ubiquitination activates the tumor suppressor p53

Guo

Cai

et al. 2019

Cell Death Differ

Self Cite

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Blocking p53 ubiquitination through disrupting its interaction with MDM2 or inhibiting the MDM2 catalytic activity is the central mechanism by which the tumor suppressor p53 is activated in response to genotoxic challenges. Although MDM2 is first characterized as the major E3 ubiquitin ligase for p53, it can also catalyze the conjugation of ubiquitin moieties to other proteins (e.g., activating transcription factor 3, or ATF3). Here we report that ATF3 can act as an ubiquitin "trap" and competes with p53 for MDM2-mediated ubiquitination. While ATF3-mediated p53 stabilization required ATF3 binding to the MDM2 RING domain, we demonstrated that ATF3 ubiquitination catalyzed by MDM2 was indispensable for p53 activation in response to DNA damage. Moreover, a cancer-derived ATF3 mutant (R88G) devoid of ubiquitination failed to prevent p53 from MDM2-mediated degradation and thus was unable to activate the tumor suppressor. Therefore, we have identified a previously-unknown mechanism that can activate p53 in the genotoxic response.

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Working title: Molecular involvement of p53‐MDM2 interactome in gastrointestinal cancers

Yedla,

Bhamidipati,

Syed

et al. 2024

Cell Biochemistry & Function

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The interaction between murine double minute 2 (MDM2) and p53, marked by transcriptional induction and feedback inhibition, orchestrates a functional loop dictating cellular fate. The functional loop comprising p53‐MDM2 axis is made up of an interactome consisting of approximately 81 proteins, which are spatio‐temporally regulated and involved in DNA repair mechanisms. Biochemical and genetic alterations of the interactome result in dysregulation of the p53‐mdm2 axis that leads to gastrointestinal (GI) cancers. A large subset of interactome is well known and it consists of proteins that either stabilize p53 or MDM2 and proteins that target the p53‐MDM2 complex for ubiquitin‐mediated destruction. Upstream signaling events brought about by growth factors and chemical messengers invoke a wide variety of posttranslational modifications in p53‐MDM2 axis. Biochemical changes in the transactivation domain of p53 impact the energy landscape, induce conformational switching, alter interaction potential and could change solubility of p53 to redefine its co‐localization, translocation and activity. A diverse set of chemical compounds mimic physiological effectors and simulate biochemical modifications of the p53‐MDM2 interactome. p53‐MDM2 interactome plays a crucial role in DNA damage and repair process. Genetic aberrations in the interactome, have resulted in cancers of GI tract (pancreas, liver, colorectal, gastric, biliary, and esophageal). We present in this article a review of the overall changes in the p53‐MDM2 interactors and the effectors that form an epicenter for the development of next‐generation molecules for understanding and targeting GI cancers.

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The Stress-responsive Gene ATF3 Mediates Dichotomous UV Responses by Regulating the Tip60 and p53 Proteins

Cited by 25 publications

References 41 publications

Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

Competitive ubiquitination activates the tumor suppressor p53

Working title: Molecular involvement of p53‐MDM2 interactome in gastrointestinal cancers

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