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Several direct target genes of the p53 tumor suppressor have been identified within pathways involved in viral sensing, cytokine production, and inflammation, suggesting a potential role of p53 in antiviral immunity. The increasing need to identify immune factors to devise host-targeted therapies against pandemic influenza A virus (IAV), led us to investigate the role of endogenous wt p53 on the immune response to IAV. We observed that the absence of p53, resulted in delayed cytokine and antiviral gene responses in lung and bone marrow, decreased dendritic cell (DC) activation and reduced IAV-specific CD8+ T cell immunity. Consequently, p53−/− mice showed a more severe IAV-induced disease compared to their wt counterparts. These findings establish that p53 influences the antiviral response to IAV, affecting both innate and adaptive immunity. Thus, in addition to its established functions as a tumor suppressor gene, p53 is serves as an IAV host antiviral factor that might be modulated to improve anti-IAV therapy and vaccines.

Present evidence suggests that E2F2 may act both as a suppressor and promoter of proliferation, depending on the cellular context. We used a loss-of-function mutant mouse model to investigate the function of E2F2 in liver regeneration after partial hepatectomy, a paradigm of cell-cycle progression. Liver mass recovery and histology were examined over 9 days in 70% hepatectomized E2F2Ϫ/Ϫ and wild-type animals. Transcriptome analysis was performed in quiescent and 48-h regenerating liver samples. TIGR MultiExperiment Viewer was used for the statistical analysis of microarray data, significance was determined by Fischer, and P values were adjusted applying BenjaminiHochberg multiple-testing correction. We show that E2F2 is required for adult hepatocyte proliferation and for timely liver regeneration, as disruption of the E2F2 gene in hepatocytes leads to a reduced rate of S-phase entry and to delayed liver regeneration. Transcriptome analysis followed by ontological classification of differentially expressed genes and gene-interaction network analysis indicated that the majority of genes involved in normal liver regeneration were related to biosynthetic and catabolic processes of all major biomolecules as well as cellular location and intracellular transport, confirming the complex nature of the regeneration process. Remarkably, transcripts of genes included in functional categories that are crucial for cell cycle, apoptosis and wound-healing response, and fibrosis were absent in the transcriptome of posthepatectomized E2F2 Ϫ/Ϫ mice. Our results indicate that the transcriptional activity of E2F2 contributes to promote adult hepatocyte proliferation and liver regeneration. cell cycle; transcriptome; liver repair; partial hepatectomy THE E2F TRANSCRIPTION FACTORS are key regulators of cell proliferation and rate-limiting factors in the S-phase entry, as they regulate the expression of many genes involved in the G 1 /S transition. According to the most accepted model of cell-cycle control, unphosphorylated retinoblastoma tumor suppressor protein (pRb) binds to E2F in G 0 /G 1 , forming a complex that actively represses E2F-responsive genes. In late G 1 pRb is inactivated because of phosphorylation by cyclin-dependent kinases, releasing free E2Fs that activate the expression of their target genes (4,12,42).The E2F family is presently composed of nine members encoded by eight different genes (E2F1-8) (4,12,20,42).Members of E2F family can be classified into "activators" (E2F1-3a) and "repressors" (E2F3b-8). Activator E2Fs are considered potent activators of transcription and positive regulators of the cell cycle. Overexpression of any of these activator E2Fs is sufficient to promote G 1 /S transition and DNA replication in immortalized, quiescent rodent fibroblasts in the absence of growth factors (23). However, there is increasing evidence that they may also act as transcriptional repressors (2,7,18,28). E2F1 seems to act both as an oncogene and as a tumor suppressor in the liver (6) but was found not to be essential f...

Lipid metabolism rearrangements in nonalcoholic fatty liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocellular carcinoma (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here, we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expressions were increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were also increased and positively correlated. E2f1−/− and E2f2−/− mice were resistant to DEN–HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN–HFD in E2f1−/− and E2f2−/− mice enhanced fatty acid oxidation (FAO) and increased expression of Cpt2, an enzyme essential for FAO, whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following E2f2 knockdown in liver, and overexpression of E2f2 elicited opposing effects. E2F2 binding to the Cpt2 promoter was enhanced in DEN–HFD-administered mouse livers compared with controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expressions inversely correlated with CPT2 expression. Collectively, these results indicate that activation of the E2F1–E2F2–CPT2 axis provides a lipid-rich environment required for hepatocarcinogenesis. Significance: These findings identify E2F1 and E2F2 transcription factors as metabolic drivers of hepatocellular carcinoma, where deletion of just one is sufficient to prevent disease.