The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice.
Name:
Buitrago-Molina et al_final.pdf
Size:
255.8Kb
Format:
PDF
Description:
original manuscript
Name:
Supplementary Materials and ...
Size:
81.53Kb
Format:
PDF
Description:
supplementary material and methods
Average rating
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Star rating
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Authors
Buitrago-Molina, Laura ElisaMarhenke, Silke
Longerich, Thomas
Sharma, Amar Deep
Boukouris, Aristeidis E
Geffers, Robert

Guigas, Bruno
Manns, Michael P
Vogel, Arndt
Issue Date
2013-09
Metadata
Show full item recordAbstract
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).Citation
The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice. 2013, 58 (3):1143-52 HepatologyAffiliation
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.Journal
Hepatology (Baltimore, Md.)PubMed ID
23526443Type
ArticleLanguage
enISSN
1527-3350ae974a485f413a2113503eed53cd6c53
10.1002/hep.26412
Scopus Count
The following license files are associated with this item:
Related articles
- p21 promotes sustained liver regeneration and hepatocarcinogenesis in chronic cholestatic liver injury.
- Authors: Marhenke S, Buitrago-Molina LE, Endig J, Orlik J, Schweitzer N, Klett S, Longerich T, Geffers R, Sánchez Muñoz A, Dorrell C, Katz SF, Lechel A, Weng H, Krech T, Lehmann U, Dooley S, Rudolph KL, Manns MP, Vogel A
- Issue date: 2014 Sep
- Dynamic and coordinated regulation of KEAP1-NRF2-ARE and p53/p21 signaling pathways is associated with acetaminophen injury responsive liver regeneration.
- Authors: Fan X, Chen P, Tan H, Zeng H, Jiang Y, Wang Y, Wang Y, Hou X, Bi H, Huang M
- Issue date: 2014 Sep
- Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation.
- Authors: Hui L, Zatloukal K, Scheuch H, Stepniak E, Wagner EF
- Issue date: 2008 Dec
- p21 ablation in liver enhances DNA damage, cholestasis, and carcinogenesis.
- Authors: Ehedego H, Boekschoten MV, Hu W, Doler C, Haybaeck J, Gaβler N, Müller M, Liedtke C, Trautwein C
- Issue date: 2015 Mar 15
- Rapamycin delays tumor development in murine livers by inhibiting proliferation of hepatocytes with DNA damage.
- Authors: Buitrago-Molina LE, Pothiraju D, Lamlé J, Marhenke S, Kossatz U, Breuhahn K, Manns MP, Malek N, Vogel A
- Issue date: 2009 Aug