Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development

Marhenke, Silke; Lamlé, Jutta; Buitrago‐Molina, Laura Elisa; Cañón, José Manuel Fernández; Geffers, Robert; Finegold, Milton J.; Sporn, Michael B.; Yamamoto, Masayuki; Manns, Michael P.; Grompe, Markus; Vogel, Arndt

doi:10.1002/hep.22391

Cited by 35 publications

(27 citation statements)

References 28 publications

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“…Nrf2 is a transcription factor, which regulates a battery of antioxidants and other cytoprotective genes in many tissues . Importantly, we have shown a high mortality and accelerated tumor development in mice with a targeted deletion of Nrf2 in Fah‐deficient mice . Thus, our data suggest that the compensatory induction of Sestrin2 does not only inhibit mTOR‐mediated hepatocyte proliferation, it also enhances the Nrf2‐regulated oxidative stress response, thereby protecting mice against subsequent injury and tumor development.…”

Section: Discussionmentioning

confidence: 65%

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The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice

et al. 2013

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Hepatocellular carcinoma (HCC) frequently arises in the context of chronic injury that promotes DNA damage and chromosomal aberrations. The cyclin‐dependent kinase inhibitor p21 is an important transcriptional target of several tumor suppressors, which promotes cell cycle arrest in response to many stimuli. The aim of this study was to further delineate the role of p21 in the liver during moderate and severe injury and to specify its role in the initiation and progression of HCC. Deletion of p21 led to continuous hepatocyte proliferation in mice with severe injury allowing animal survival but also facilitated rapid tumor development, suggesting that control of compensatory proliferation by high levels of p21 is critical to the prevention of tumor development. Unexpectedly, however, liver regeneration and hepatocarcinogenesis was impaired in p21‐deficient mice with moderate injury. Mechanistically, loss of p21 was compensated by activation of Sestrin2, which impaired mitogenic mammalian target of rapamycin (mTOR) signaling and activated cytoprotective Nrf2 signaling. Conclusion: The degree of liver injury and the strength of p21 activation determine its effects on liver regeneration and tumor development in the liver. Moreover, our data uncover a molecular link in the complex mTOR, Nrf2, and p53/p21‐signaling network through activation of Sestrin2, which regulates hepatocyte proliferation and tumor development in mice with liver injury. (Hepatology 2013;53:1143–1152)

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Section: Discussionmentioning

confidence: 65%

“…HT1 is characterized by an extremely high susceptibility to liver cancer. A murine model of Fah deficiency has been developed that represents all phenotypic and biochemical manifestations of the human disease on an accelerated time scale …”

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confidence: 99%

The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice

et al. 2013

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“…A). We have previously shown that accumulating FAA induces OS and an OS response mediated by nuclear factor‐erythroid 2‐related factor 2 (NRF2) . Protein expression of two well‐known targets of NRF2, NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO‐1), were strongly induced in chronically injured Fah − / − mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

The BH3‐only protein BID impairs the p38‐mediated stress response and promotes hepatocarcinogenesis during chronic liver injury in mice

et al. 2015

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Apoptosis is critical for maintaining tissue homeostasis, and apoptosis evasion is considered as a hallmark of cancer. However, increasing evidence also suggests that proapoptotic molecules can contribute to the development of cancer, including liver cancer. The aim of this study was to further clarify the role of the proapoptotic B-cell lymphoma 2 homology domain 3 (BH3)-only protein BH3 interacting-domain death agonist (BID) for chronic liver injury (CLI) and hepatocarcinogenesis (HCG). Loss of BID significantly delayed tumor development in two mouse models of Fah-mediated and HBsTg-driven HCG, suggesting a tumor-promoting effect of BID. Liver injury as well as basal and mitogen-stimulated hepatocyte proliferation were not modulated by BID. Moreover, there was no in vivo or in vitro evidence that BID was involved in DNA damage response in hepatocytes and hepatoma cells. Our data revealed that CLI was associated with strong activation of oxidative stress (OS) response and that BID impaired full activation of p38 after OS. Conclusion: We provide evidence that the tumor-promoting function of BID in CLI is not related to enhanced proliferation or an impaired DNA damage response. In contrast, BID suppresses p38 activity and facilitates malignant transformation of hepatocytes. (HEPATOLOGY 2015;62:816-828) L iver cancer is the fifth-most common cancer in men and the ninth in women worldwide. 1 Among all cancer types, it is the second-leading cause of cancer 1 and therefore a considerable health problem. Patients with hepatocellular carcinoma (HCC), the predominant form of liver cancer, 2 are confronted with limited therapeutic options. 3 In order to develop new innovative approaches to treat and prevent tumor development in the liver, a better understanding of the underlying cellular mechanisms and molecular alterations is required.Apoptosis, the best-studied form of programmed cell death, is critical for maintaining tissue homeostasis and its deregulation is recognized as an important factor for tumorigenesis. 4,5 The decision whether a cell should live or die is largely mediated by the B-cell lymphoma 2 (BCL-2) family of anti-and proapoptotic proteins. The antiapoptotic proteins, BCL-2, BCL-2-extra large, and myeloid cell leukemia sequence 1 (MCL-1), are frequently overexpressed in HCC, 6-11 supporting the hypothesis that apoptosis resistance could contribute to Abbreviations: 4E-BP1, eIF4E binding protein 1; AKT, protein kinase B; ATM, ataxia telangiectasia mutated; BCL-2, B-cell lymphoma 2; BH3, B-cell lymphoma 2 homology domain 3; BID, BH3 interacting-domain death agonist; BrdU, bromodeoxyuridine; CLI, chronic liver injury; DEN, diethylnitrosamine; ERK, extracellular signal-regulated kinase; FAA, fumarylacetoacetate; FAH, fumarylacetoacetate hydrolase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HBsTg, HBV surface antigen transgenic; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCG, hepatocarcinogenesis; HO-1, heme oxygenase 1; IHC, immunohistochemistry; IP, immunoprecipitation; JNK, c-JUN NH2-...

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“…Several studies using Nrf2 knockout mice have shown that Nrf2 protects against chemical carcinogeninduced tumor formation in the stomach, bladder, skin, and colorectum (Kensler et al, 2007;Khor et al, 2008;Marhenke et al, 2008;Jaramillo and Zhang, 2013). The mechanism by which Nrf2 protects against chemical-induced carcinogenesis might be due in part to its ability to reduce the amount of ROS and DNA damage in cells (Hirayama et al, 2003;Morito et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Gankyrin has an antioxidative role through the feedback regulation of Nrf2 in hepatocellular carcinoma

Yang¹,

Tan²,

Yang³

et al. 2016

J Cell Biol

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Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development

Cited by 35 publications

References 28 publications

The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice

The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice

The BH3‐only protein BID impairs the p38‐mediated stress response and promotes hepatocarcinogenesis during chronic liver injury in mice

Gankyrin has an antioxidative role through the feedback regulation of Nrf2 in hepatocellular carcinoma

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