p21 in chronic and acute liver injury

p21 historically has been considered a tumor suppressor since first studies showed that p21-/-mice display spontaneous tumor formation after 16 months and additionally these mice are more sensitive to chemically induced carcinogenesis [1,2]. On the contrary, recently a potential function as an oncogene has been described for p21. For instance mice deficient for p53 spontaneously develop multiple tumors and an additional deletion of p21 lead to a significant reduction of thymic lymphomas [3]. This argues that the complete spectrum of p21 function during tumorigenesis is not clearly identified. The role of p21 has been further studied in the NEMO Δhepa mice model. The NF-κB pathway regulator NEMO (also known as IKKγ) has been shown to control chronic inflammation and hepatocarcinogenesis in mice. The hepatocyte specific deletion of NEMO (NEMO Δhepa), is of clinical interest as these animals develop a cascade of events which resemble the spectrum of human chronic liver disease, which leads from chronic hepatitis to liver cirrhosis and growth of hepatocellular carcinomas (HCC). Additionally, a recent study using human HCC tissue found a downregulation of NEMO in tumor tissue, further supporting the translational relevance of the NEMO Δhepa mice model [4]. The deletion of NEMO in hepatocytes triggers increased p21 expression [5,6]. In order to study the relevance of p21 overexpression for disease progression of NEMO Δhepa livers, double knockout (NEMO Δhepa /p21-/-) mice carrying a hepatocyte specific deletion for NEMO and an additional constitutional deletion for p21 were generated. Although p21 is a cell cycle inhibitor its deletion had no impact on cell proliferation in 8 week-old NEMO Δhepa /p21-/-livers compared to NEMO Δhepa livers. This result was unexpected since p21 binds to CcnE/cdk2 and CcnA/cdk2 complexes thereby preventing progression from G 1-to S-phase. Very likely the loss of p21 expression is compensated by other cell cycle inhibitors such as p-p27 and p18. Despite the unchanged cell cycle activity in p21 deficient NEMO Δhepa livers, the cell cycle regulator CcnA2 and CcnE2 were overexpressed. However, recent studies discovered that ectopic overexpression of CcnA or CcnE in mouse embryonic fibroblast (MEFs) lead to an increase in DNA double strand breakage [7]. Therefore the enhanced liver injury caused by exacerbation of DNA damage in p21-deficient NEMO Δhepa mice could be explained by elevated CcnA2 and CcnE2 expression. The DNA double strand breakage was quantified by pH2AX Immunofluorescence staining. p21 is not only protective against DNA damage in the chronic …