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

2.50
Hdl Handle:
http://hdl.handle.net/10033/303462
Title:
The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice.
Authors:
Buitrago-Molina, Laura Elisa; Marhenke, Silke; Longerich, Thomas; Sharma, Amar Deep; Boukouris, Aristeidis E; Geffers, Robert ( 0000-0003-4409-016X ) ; Guigas, Bruno; Manns, Michael P; Vogel, Arndt
Abstract:
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).
Affiliation:
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
Citation:
The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice. 2013, 58 (3):1143-52 Hepatology
Journal:
Hepatology (Baltimore, Md.)
Issue Date:
Sep-2013
URI:
http://hdl.handle.net/10033/303462
DOI:
10.1002/hep.26412
PubMed ID:
23526443
Type:
Article
Language:
en
ISSN:
1527-3350
Appears in Collections:
publications of the research group genomeanalytics (GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorBuitrago-Molina, Laura Elisaen
dc.contributor.authorMarhenke, Silkeen
dc.contributor.authorLongerich, Thomasen
dc.contributor.authorSharma, Amar Deepen
dc.contributor.authorBoukouris, Aristeidis Een
dc.contributor.authorGeffers, Roberten
dc.contributor.authorGuigas, Brunoen
dc.contributor.authorManns, Michael Pen
dc.contributor.authorVogel, Arndten
dc.date.accessioned2013-10-15T12:55:57Zen
dc.date.available2013-10-15T12:55:57Zen
dc.date.issued2013-09en
dc.identifier.citationThe degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice. 2013, 58 (3):1143-52 Hepatologyen
dc.identifier.issn1527-3350en
dc.identifier.pmid23526443en
dc.identifier.doi10.1002/hep.26412en
dc.identifier.urihttp://hdl.handle.net/10033/303462en
dc.description.abstractHepatocellular 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).en
dc.language.isoenen
dc.rightsArchived with thanks to Hepatology (Baltimore, Md.)en
dc.titleThe degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice.en
dc.typeArticleen
dc.contributor.departmentDepartment of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.en
dc.identifier.journalHepatology (Baltimore, Md.)en

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