ATF-2 controls transcription of Maspin and GADD45α genes independently from p53 to suppress mammary tumors

Maekawa, Tomoko; Sano, Yuji; Shinagawa, Toshie; Rahman, Zulkanain Abdul; Sakuma, Takahiko; Nomura, Shosaku; Licht, Jonathan D.; Ishii, Shunsuke

doi:10.1038/sj.onc.1210727

Cited by 78 publications

(57 citation statements)

References 21 publications

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“…ATF-2, a JNK substrate that we show to be phosphorylated in response to cytokines (Fig. 1D), has been shown to contribute to the transcriptional regulation of GADD45␣ expression and to participate in JNK-dependent DNA repair (46,52).…”

Section: Discussionmentioning

confidence: 99%

Repair of Nitric Oxide-damaged DNA in β-Cells Requires JNK-dependent GADD45α Expression

Hughes

Meares

Chambers

et al. 2009

Journal of Biological Chemistry

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Proinflammatory cytokines induce nitric oxide-dependent DNA damage and ultimately ␤-cell death. Not only does nitric oxide cause ␤-cell damage, it also activates a functional repair process. In this study, the mechanisms activated by nitric oxide that facilitate the repair of damaged ␤-cell DNA are examined. JNK plays a central regulatory role because inhibition of this kinase attenuates the repair of nitric oxide-induced DNA damage. p53 is a logical target of JNK-dependent DNA repair; however, nitric oxide does not stimulate p53 activation or accumulation in ␤-cells. Further, knockdown of basal p53 levels does not affect DNA repair. In contrast, expression of growth arrest and DNA damage (GADD) 45␣, a DNA repair gene that can be regulated by p53-dependent and p53-independent pathways, is stimulated by nitric oxide in a JNK-dependent manner, and knockdown of GADD45␣ expression attenuates the repair of nitric oxide-induced ␤-cell DNA damage. These findings show that ␤-cells have the ability to repair nitric oxide-damaged DNA and that JNK and GADD45␣ mediate the p53-independent repair of this DNA damage.Insulin-dependent diabetes mellitus is an autoimmune disease characterized by the selective destruction of insulin-secreting pancreatic ␤-cells found in the islets of Langerhans (1). Cytokines, released from invading leukocytes during insulitis, are believed to participate in the initial destruction of ␤-cells, precipitating the autoimmune response (2, 3). Treatment of rat islets with the macrophage-derived cytokine interleukin-1 (IL -1) 2 results in the inhibition of glucose-stimulated insulin secretion and oxidative metabolism and in the induction of DNA damage that ultimately results in ␤-cell death (4 -6). Nitric oxide, produced in micromolar levels following enhanced expression of the inducible nitric-oxide synthase in ␤-cells, mediates the damaging actions of cytokines on ␤-cell function (7-9). Nitric oxide inhibits insulin secretion by attenuating the oxidation of glucose to CO 2 , reducing cellular levels of ATP and, thereby, attenuating ATP-inhibited K ϩ channel activity (10, 11). The net effect is the inhibition of ␤-cell depolarization, calcium entry, and calcium-dependent exocytosis. In addition to the inhibition of ␤-cell function, nitric oxide induces DNA damage in ␤-cells (4, 12, 13). Nitric oxide or the oxidation products N 2 O 3 and ONOO Ϫ induce DNA damage through direct strand breaks and base modification (14 -16) and by inhibition of DNA repair enzymes, thereby enhancing the damaging actions of nitric oxide (17,18).Recent studies have shown that ␤-cells maintain a limited ability to recover from cytokine-mediated damage (19,20). The addition of a nitric-oxide synthase inhibitor to islets treated for 24 h with cytokine and continued culture with the nitric-oxide synthase inhibitor and cytokine results in a time-dependent restoration of insulin secretion, mitochondrial aconitase activity, and the repair of nitric oxide-damaged DNA (20, 21). Nitric oxide plays a dual role in modifying ␤-cell respon...

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Section: Discussionmentioning

confidence: 99%

Repair of Nitric Oxide-damaged DNA in β-Cells Requires JNK-dependent GADD45α Expression

Hughes

Meares

Chambers

et al. 2009

Journal of Biological Chemistry

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“…Thus, the mechanism behind the regulation of GADD45A expression in ESCC remains unclear. Other factors, such as myc, phosphoinositide 3-kinase/AKT (23,24), activating transcription factor 2 (25) and Quercetin (26), which have been shown to regulate GADD45A expression, should be investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

GADD45A expression is correlated with patient prognosis in esophageal cancer

et al. 2015

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Abstract. The prognosis of patients with esophageal cancer remains poor, and the tumor-node-metastasis classification system is not sufficient for predicting patient prognoses. Therefore, the identification of novel predictive markers for esophageal cancer is required. The present study investigated the clinicopathological significance of growth arrest and DNA damage-inducible 45α (GADD45A) and p53 in resectable esophageal squamous cell carcinoma (ESCC). The study consisted of 62 patients with esophageal cancer who underwent surgery between 2001 and 2007. The expression of the GADD45A gene product (GADD45A) and the p53 protein was analyzed by immunohistochemistry. The correlations among GADD45A expression, clinicopathological factors and prognosis were then analyzed in the patients with ESCC. GADD45A and p53 were expressed in 56.5% (35/62) and 48.4% (30/62) of patients, respectively. The expression of GADD45A did not show a marked correlation with that of p53. However, GADD45A expression correlated with pathological stage (stage 0-I vs. stages II-IV; P=0.014) and did not correlate with the tumor (T) or node (N) status. Furthermore, patients who were positive for GADD45A exhibited a significantly higher survival rate than those who were negative for GADD45A (log-rank test, P=0.009). Multivariate analysis indicated that T status, N status and GADD45A expression were significant variables predicting survival (hazard ratio, 2.486; 95% confidence interval, 1.168-5.290; P=0.018). Overall, GADD45A expression significantly affected the survival of patients with ESCC, and the reduced expression of GADD45A was correlated with a poor prognosis following curative surgery in these patients. IntroductionThe prognosis of esophageal cancer patients remains poor, emphasizing the requirement for the development of novel treatment strategies. At present, the overall 5-year survival rate is <50%, despite the use of multimodality therapies. Numerous patients, even those with early-stage disease, develop local recurrence of tumors or distant metastasis within a short time period after surgery. To develop novel treatment strategies, it is important to understand the biological behavior of esophageal cancer. Recent studies have found that a number of genes and molecules show involvement in the origin and/or progression of esophageal cancer, including tumor protein p53 (1), deleted in esophageal cancer 1 (2), deleted in colorectal cancer (3), deleted in lung cancer 1 (4), cyclin D1 (5), adenomatous polyposis coli (6) and survivin (7). However, the exact mechanisms underlying esophageal squamous cell carcinoma (ESCC) development and progression remain unclear.The p53 gene is required for the proper induction of the G 1 checkpoint and functions to upregulate growth arrest and DNA damage-inducible 45α (GADD45A) and WAF1/p21 expression (8). Additionally, GADD45A is a downstream mediator of p53 and is able to deactivate p53, thereby contributing to cell cycle regulation through binding with cyclin-dependent kinases and proliferating cell nuc...

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“…Consistently, several stress signals that induce maspin expression also induced more differentiated phenotypes [16,[54][55][56]. Furthermore, epigenetic treatment of prostate cancer cell lines with trichostatin A, a histone deacetylase (HDAC) inhibitor, led to induction of maspin mRNA [20,50]. Re-expression of maspin using demethylating agents and HDAC inhibitors has been confirmed in additional studies [50,57].…”

Section: Therapeutic Application Of Maspinmentioning

confidence: 48%

“…Expression of the antioxidant manganese superoxide dismutase in prostate cells led to an increase in stability of maspin mRNA, and this effect persisted in the presence of wild-type or mutant p53 [19]. Furthermore, the activating transcription factor (ATF-2) was shown to induce maspin expression independently of p53 by binding to a CRE-like sequence downstream of the transcription start site [20]. In addition, other members of the p53 family, specifically the p63 isoform TAp63γ, induce expression of maspin by binding to the same consensus p53 promoter element and can substitute for activation in the absence of p53 [21].…”

Section: Regulation Of Maspin Expressionmentioning

confidence: 94%

Maspin Expression and its Metastasis Suppressing Function in Prostate Cancer

Shankar¹,

Candamo²,

MacLennan³

et al. 2016

Prostate Cancer - Leading-Edge Diagnostic Procedures and Treatments

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Mammary Serine Protease Inhibitor (Maspin) is a unique member of the serpin family with tumor suppressive properties. Maspin is a secreted protein encoded by a class II tumor suppressor gene, expressed in normal prostate luminal and basal cells but reduced or absent in prostate cancer. Currently, there is a consensus that maspin expression in prostate cancer is an indicator of a better prognosis and is a predictive marker for therapeutic response in prostate cancer. Experimental evidence consistently indicates that maspin suppresses tumor growth, invasion, and metastasis and promotes apoptosis in cancer cells. In this chapter, we discuss regulation of maspin expression, binding partners of maspin, and pathways through which maspin exerts its tumor suppressive properties. In addition, we summarize the progress that investigators have made in clarifying the role of maspin in prostate cancer biology and in assessing its role as a diagnostic marker and therapeutic agent.

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ATF-2 controls transcription of Maspin and GADD45α genes independently from p53 to suppress mammary tumors

Cited by 78 publications

References 21 publications

Repair of Nitric Oxide-damaged DNA in β-Cells Requires JNK-dependent GADD45α Expression

Repair of Nitric Oxide-damaged DNA in β-Cells Requires JNK-dependent GADD45α Expression

GADD45A expression is correlated with patient prognosis in esophageal cancer

Maspin Expression and its Metastasis Suppressing Function in Prostate Cancer

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