Gadd45 in Stress Signaling, Cell Cycle Control, and Apoptosis

Salvador, Jesús M.; Brown-Clay, Joshua D.; Fornace, Albert J.

doi:10.1007/978-1-4614-8289-5_1

Cited by 296 publications

(267 citation statements)

References 82 publications

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“…GADD45A and CDKN1A (p21), both of which regulate cell cycle arrest 28,29 and are induced by p53, were significantly upregulated in v2-depleted cells compared with controls in a p53+, but not p53i, background (Figure 4d and Supplementary Figure S3B), suggesting they may contribute to the p53-dependent S-phase arrest in v2-depleted cells. On the other hand, proliferating cell nuclear antigen (PCNA), which is required for progression of DNA replication, 30 was significantly reduced in TP8i cells in both the p53+ and p53i settings ( Figure 5e).…”

Section: Resultsmentioning

confidence: 99%

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

et al. 2016

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Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a stress-response gene that has been associated with cancer, but no studies have differentiated among or defined the regulation or function of any of its several recently described expression variants. We found that TNFAIP8 variant 2 (v2) is overexpressed in multiple human cancers, whereas other variants are commonly downregulated in cancer (v1) or minimally expressed in cancer or normal tissue (v3-v6). Silencing v2 in cancer cells induces p53-independent inhibition of DNA synthesis, widespread binding of p53, and induction of target genes and p53-dependent cell cycle arrest and DNA damage sensitization. Cell cycle arrest induced by v2 silencing requires p53-dependent induction of p21. In response to the chemotherapeutic agent doxorubicin, p53 regulates v2 through binding to an intragenic enhancer, together indicating that p53 and v2 engage in complex reciprocal regulation. We propose that TNFAIP8 v2 promotes human cancer by broadly repressing p53 function, in essence offsetting p53-dependent tumor suppression. Cell Death and Differentiation (2017) 24, 181-191; doi:10.1038/cdd.2016 published online 11 November 2016 Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is the founding member of a recently described family of environmental stress response genes that are induced by TNFα. TNFAIP8 has been shown to promote or inhibit apoptosis, depending on cell type and context. 1,2 Although little is known about TNFAIP8, it has recently been found to be overexpressed in a wide range of human cancers. Some studies have suggested protumor functions for TNFAIP8, including enhancement of cell survival, proliferation, and metastasis [3][4][5][6][7][8][9] and resistance to cancer chemotherapeutics in mice. 4,10Nonetheless, nothing is known about how TNFAIP8 influences responses to DNA damage in cancer cells. Moreover, several transcript variants from the TNFAIP8 gene were recently registered in the NCBI reference sequence database, but no study to date has differentiated among them or defined the factors that govern their expression.The tumor suppressor p53 is a transcription factor that regulates many biological processes through its target gene network. Some of the well-characterized p53 target genes including p21/CDKN1A, growth arrest and DNA damageinducible 45a (GADD45A) and Bcl-2-like protein 4 (BAX) together promote senescence, cell cycle arrest, and apoptosis, all of which may contribute to the tumor suppressing functions of p53. 11,12Additional noncanonical tumorsuppressive pathways from p53 have recently been identified. [13][14][15] Improved characterization of the p53 DNAbinding sequence with modern sequencing techniques has led to the identification of a rapidly expanding list of p53 target genes. [16][17][18] Continued identification of these genes and characterization of their mechanisms of regulation and function will be critical to a full understanding of p53 and for full realization of opportunities to intervene upon p53 in cancer.Here, we identify ...

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Section: Resultsmentioning

confidence: 99%

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

et al. 2016

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“…This observation suggests that modulation of translation efficiency might reinforce the activation of p53-dependent apoptosis, a process that could be important given the generally weaker transcriptional control of p53 target genes in the apoptosis group. 24 We validated by qPCR TRIAP1, 25 TRAF4 26 and GADD45G 27 (the full list of genes is presented in Supplementary Figure S3A). According to ChIP-seq data on MCF7 cells, these genes are direct p53 targets.…”

Section: Resultsmentioning

confidence: 99%

p53-directed translational control can shape and expand the universe of p53 target genes

et al. 2014

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The increasing number of genome-wide transcriptome analyses focusing on p53-induced cellular responses in many cellular contexts keeps adding to the already numerous p53-regulated transcriptional networks. To investigate post-transcriptional controls as an additional dimension of p53-directed gene expression responses, we performed a translatome analysis through polysomal profiling on MCF7 cells upon 16 hours of doxorubicin or nutlin-3a treatment. The comparison between the transcriptome and the translatome revealed a considerable level of uncoupling, characterized by genes whose transcription variations did not correlate with translation variations. Interestingly, uncoupled genes were associated with apoptosis, DNA and RNA metabolism and cell cycle functions, suggesting that post-transcriptional control can modulate classical p53-regulated responses. Furthermore, even for well-established p53 targets that were differentially expressed both at the transcriptional and translational levels, quantitative differences between the transcriptome, subpolysomal and polysomal RNAs were evident. As we searched mechanisms underlying gene expression uncoupling, we identified the p53-dependent modulation of six RNA-binding proteins, where hnRNPD (AUF1) and CPEB4 are direct p53 transcriptional targets, whereas SRSF1, DDX17, YBX1 and TARDBP are indirect targets (genes modulated preferentially in the subpolysomal or polysomal mRNA level) modulated at the translational level in a p53-dependent manner. In particular, YBX1 translation appeared to be reduced by p53 via two different mechanisms, one related to mTOR inhibition and the other to miR-34a expression. Overall, we established p53 as a master regulator of translational control and identified new p53-regulated genes affecting translation that can contribute to p53-dependent cellular responses.

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“…Increased expression of H2AFX and BRCA-1 in the PhIP-treated group as well as data from comet assays, ROS monitoring and immunofluorescence with anti-DNA adduct antibodies support this idea [7]. Previous studies have shown that BRCA-1, P-53 and other tumor suppressor genes are able to increase GADD-45 expression [16][17][18]. Catalase and GADD-45 are associated with the FOXO pathway; however, these two genes perform different functions of detoxification and DNA repair, respectively.…”

Section: Brief Reportmentioning

confidence: 77%

Curcumin Inhibit PhIP-Induced Carcinogenicity by Regulating Expression of Nrf2 and FOXO Targets, and BRCA-1 and P16 Expression in Breast Epithelial Cells

Jain

2015

J Carcinog Mutagen

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PhIP (Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine) is a heterocyclic amine (HCA) which is formed when meat products are cooked at high temperature. PhIP is known for its genotoxic and carcinogenic effects causing several types of cancer, including breast cancer. HCA causes multifold cytotoxic effect, for example metabolism of PhIP leads to ROS production, and PhIP metabolites produce DNA adduct and DNA strand breaks [1][2][3][4]. Breast epithelial cells contain all the machinery to metabolize HCA and the genotoxic effects of these metabolites may lead to breast cancer [1].The prevention of cancer through diet is categorized as one of the most effective ways to reduce cancer incidence [5]. We hypothesized that curcumin may be a potential food additive that may be inhibitory to PhIP-induced carcinogenicity by inhibiting ROS production, DNA adduct formation and DNA strand breaks. We developed a model system using the breast epithelial cells (MCF-10A) to screen several dietary additives to identify phytochemical that is capable to inhibit PhIP cytotoxicity. Curcumin a polyphenol and major component of the Indian spice turmeric, which is used in various food preparations, is known to inhibit cell proliferation and has anticancer effects [6]. In this brief report, we describe how curcumin inhibits PhIP-induced ROS production, DNA adduct formation and DNA damage in MCF-10A cells.MCF-10A human breast epithelial cells were cultured in a humidified incubator at 37°C under 5% CO 2 atmospheric conditions in RPMI media supplemented with 10 µg/ml insulin, 20 ng/ml epidermal growth factor, 10 mg/ml hydrocortisone, 5% horse serum and 1% penicillin-streptomycin (10,000 U/ml). Cells were treated with or without PhIP (50 and 250 µM) in the presence or absence of curcumin (150 µM) and cell viability determined using the cell counting kit-8 (Dojindo Laboratories). Cells were pretreated with curcumin 15 minutes prior to dosing with PhIP (50 or 250 µM). MCF 10A cells viability is decreased when treated with PhIP in a dose dependent manner. Results shows that curcumin at a concentration of 150 µM significantly inhibited PhIP-induced reductions in viability at 24 h, with cells treated with 50 µM PhIP plus 150 µM curcumin, and 250 µM PhIP plus 150 µM curcumin (Table 1a).The antioxidant capacity of curcumin was analyzed in the absence and in the presence of the PhIP, a well-known peroxidant agent. Its efficiency was evaluated in terms of inhibition of intracellular reactive oxygen species (ROS) production induced spontaneously or in the presence of PhIP. Intracellular free radical species were detected by measuring the fluorescence intensity values (using a Biotek, Synergy HT instrument with an excitation 475-495 and emission 518-528) due to the oxidation of DCF and expressed as relative fluorescence units (RFU).In the absence of PhIP, ROS production was limited but increased significantly in the presence of PhIP in a dose-dependent manner. Cotreatment of MCF-10A cells with curcumin resulted in a significant decrease in PhIP-induced RO...

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Gadd45 in Stress Signaling, Cell Cycle Control, and Apoptosis

Cited by 296 publications

References 82 publications

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

p53-directed translational control can shape and expand the universe of p53 target genes

Curcumin Inhibit PhIP-Induced Carcinogenicity by Regulating Expression of Nrf2 and FOXO Targets, and BRCA-1 and P16 Expression in Breast Epithelial Cells

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