Unexpectedly, however, liver regeneration and hepatocarcinogenesis was impaired in p21-deficient mice with moderate PD-0332991 supplier 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 Ivacaftor in vitro 2013;53:1143–1152) Hepatocellular carcinoma (HCC) is frequently associated with exposure to extrinsic factors that directly or indirectly induce DNA damage and chromosomal aberrations. Accumulation of DNA damage in hepatocytes ultimately leads to expanding foci of dysplastic hepatocytes, which progress to liver cancer if not rigorously controlled. ATM and ATR are serine/threonine kinases that sense DNA damage

and coordinate DNA damage response pathways, most importantly p53. Activated p53 can inhibit proliferation to allow repair of DNA damage or trigger apoptosis if DNA damage is irreparable. p21 is one of the main effectors of p53 that induces cell cycle arrest and senescence in response to triggers such as DNA damage and telomere shortening by inhibiting the activity of cyclin-dependent kinase (CDK)–cyclin complexes and proliferating cell nuclear antigen.[1] Due to its ability

to induce growth arrest and as one of the main targets of several tumor suppressors, p21 was also considered as a potential tumor suppressor. Furthermore, several genetic studies in mice confirmed the importance of p21 for the regulation of liver regeneration and its ability to delay tumor development in the liver.[2-5] this website The simple view on p21 as a tumor suppressor has been complicated, however, by findings that p21 can exhibit oncogenic activities in certain contexts. The first evidence for a protumorigenic role of p21 came from observations that p21 suppresses apoptosis of thymic lymphoma cells, thereby accelerating tumor growth.[6] More recent data suggest that p21 may also induce proliferation of cancer cells by promoting the assembly of type D cyclins with CDK4 and CDK6.[7] The aim of this study was to further delineate the role of p21 in the liver during acute and chronic injury and to specify its role for the initiation and progression of HCC. Mice with a targeted genetic deletion of p21 were crossed into a mouse model of hereditary tyrosinemia type 1 (HT1).