DNA damage induced activation of Cygb stabilizes p53 and mediates G1 arrest

John, Rince; Chand, Vaibhav; Chakraborty, Sankalpa; Jaiswal, Neha; Nag, Alo

doi:10.1016/j.dnarep.2014.09.003

Cited by 20 publications

(24 citation statements)

References 29 publications

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“…Our observation of Cygb overexpression causing retardation of cell growth and proliferation (Fig. A‐C, G and H) is yet another evidence that is in line with literature and our recent findings on Cygb‐mediated cell cycle arrest . Our previous work also identified the transcription factor, p53 as a novel interactor of Cygb and this investigation not only supports the cell cycle‐related functions of Cygb but also alludes to its nuclear functions.…”

Section: Discussionsupporting

confidence: 91%

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Cell cycle‐dependent regulation of cytoglobin by Skp2

et al. 2017

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Cytoglobin (Cygb) is a cellular haemoprotein belonging to the globin family with ambiguous biological functions. Downregulation of Cygb in many cancers is indicative of its tumour-suppressive role. This is the first report showing the cell cycle regulation of Cygb, which was found to peak at G1 and rapidly decline in S phase. Importantly, Skp2-mediated degradation of Cygb was identified as the key mechanism for controlling its oscillating levels during the cell cycle. Moreover, overexpression of Cygb stimulates hypophosphorylation of Rb causing delayed cell cycle progression. Overall, the study reveals a novel mechanism for the regulated expression of Cygb and also assigns a new role to Cygb in cell cycle control.

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Section: Discussionsupporting

confidence: 91%

“…However, the exact molecular mechanism underlying the tumour suppressor activity of Cygb is only partially understood. Recent findings from our laboratory also highlight the role of Cygb in DNA damage response and maintenance of genomic stability . These findings support the role of Cygb in cell cycle arrest upon genotoxic stress in a p53‐dependent manner.…”

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confidence: 79%

Cell cycle‐dependent regulation of cytoglobin by Skp2

et al. 2017

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“…31,32 Interestingly, the nuclear localization of Cygb suggests additional undisclosed functions in gene regulation, possibly via interactions with transcriptional modulators. 33,34 In vitro and in vivo studies have documented increased Cygb expression under the conditions of oxygen deficiency 35,36 and oxidative stress. The presence of hypoxia-inducible factor-1-binding sites at the CYGB promoter reinforces the possible involvement of CYGB in the protection of cells during hypoxia as previously reported in hepatic stellate cells, human SH-SY5Y neuroblastoma cells 37 and MIN6 pancreatic cells; 38 however, the underlying molecular mechanisms remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer

et al. 2015

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During physiological aerobic metabolism, the epidermis undergoes significant oxidative stress as a result of the production of reactive oxygen species (ROS). To maintain a balanced oxidative state, cells have developed protective antioxidant systems, and preliminary studies suggest that the transcriptional factor p63 is involved in cellular oxidative defence. Supporting this hypothesis, the ΔNp63α isoform of p63 is expressed at high levels in the proliferative basal layer of the epidermis. Here we identify the CYGB gene as a novel transcriptional target of ΔNp63 that is involved in maintaining epidermal oxidative defence. The CYGB gene encodes cytoglobin, a member of the globin protein family, which facilitates the diffusion of oxygen through tissues and acts as a scavenger for nitric oxide or other ROS. By performing promoter activity assays and chromatin immunoprecipitation, reverse transcriptase quantitative PCR and western blotting analyses, we confirm the direct regulation of CYGB by ΔNp63α. We also demonstrate that CYGB has a protective role in proliferating keratinocytes grown under normal conditions, as well as in cells treated with exogenous hydrogen peroxide. These results indicate that ΔNp63, through its target CYGB has an important role in the cellular antioxidant system and protects keratinocytes from oxidative stress-induced apoptosis. The ΔNp63-CYGB axis is also present in lung and breast cancer cell lines, indicating that CYGB-mediated ROS-scavenging activity may also have a role in epithelial tumours. In human lung cancer data sets, the p63-CYGB interaction significantly predicts reduction of patient survival.

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“…Cygb is significantly deregulated by its promoter hypermethylation in most malignancies, 26,28,29 thereby promoting tumorigenesis and progression. [16][17][18][19][20][21][30][31][32] In this study, we found that Cygb is significantly deregulated in human HCC tissues, as compared with these adjacent non-tumor tissues and hepatolithiasis tissues ( Figure 1A-C), Cygb decrease promotes HCC proliferation, whereas Cygb restoration inhibits cell proliferation (Figure 2A-D). We proposed that Cytoglobin functions as tumor suppressor, and its decrease is negatively associated with HCC progression.…”

Section: Discussionmentioning

confidence: 63%

Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

Zhang

Pei

Yang

et al. 2018

Molecular Carcinogenesis

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Cancer stem cells (CSCs) account for tumor self‐renewal and heterogeneity. Oxidative‐nitrosative stress (ONS) is an independent etiologic factor throughout tumorigenesis. Emerging evidences indicated that the interaction of ONS with CSCs contributes to tumor progression and resistance to chemoradiotherapy. Cytoglobin (Cygb) is a member of human hexacoordinate hemoglobin family and acts as a dynamic mediator of redox homeostasis. We observed that Cygb is significantly deregulated in human hepatocellular carcinoma (HCC) tissue and its decrease aggravates the growth of liver cancer stem cells (LCSCs) and increases the subpopulation of CD133(+) LCSCs. Cygb restoration inhibits HCC proliferation and LCSC growth, and decreases the subpopulation of CD133 (+) LCSCs in vitro. We found that Cygb absence promotes LCSC phenotypes and PI3 K/AKT activation, whereas Cygb restoration inhibits LCSC phenotypes and PI3 K/AKT activation. Furthermore, exogenous antioxidants can eliminate the inhibitory effect of Cygb to LCSC growth and phenotypes, as well as PI3 K/AKT activation. Collectively, this study demonstrated that cytoglobin functions as a tumor suppressor and targets CSCs at an ONS‐dependent manner. Thus, Cygb restoration could be a novel and promising therapeutic strategy against HCC with aberrant ROS/RNS accumulation.

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DNA damage induced activation of Cygb stabilizes p53 and mediates G1 arrest

Cited by 20 publications

References 29 publications

Cell cycle‐dependent regulation of cytoglobin by Skp2

Cell cycle‐dependent regulation of cytoglobin by Skp2

ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer

Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

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