4, 5 Notably, even in spite of the continuous

presence of growth inducers, the liver of non–genetically modified rodents never exceeds doubling of its mass, indicating that a precise regulation of tissue size must exist to prevent its further growth, likely incompatible with the survival of the organism. LY2109761 Many xenobiotics able to induce liver enlargement are ligands of nuclear receptors of the steroid/thyroid receptor superfamily6 and, interestingly, are also liver nongenotoxic carcinogens.7–9 In spite of several studies, the key molecular events that govern the tumoral potency of ligands of nuclear receptors are still unclear. The breakthrough that many compounds with liver tumor–promoting ability are also potent inducers of hepatocyte proliferation led to the hypothesis that the mechanisms by which these Imatinib in vivo agents cause liver neoplasia are a consequence of their mitogenic capacity that ultimately results in an increased rate of mutation.10 However, this hypothesis has been questioned by the findings that the proliferative response of the liver to these mitogens is lost very shortly,11, 12 suggesting that the hyperplastic liver becomes refractory to further mitogenic stimuli. These findings

also suggest that the tumors arising in these enlarged livers may be the consequence of the escape of genetically damaged cells from the regulatory Exoribonuclease mechanisms governing the size of the organ. Thus, the identification of the molecular mechanisms responsible for the refractoriness of the enlarged liver to further mitogenic stimuli is critical for improving our knowledge of the control of organ size, and also for determining whether dysregulation of these pathways is a possible mechanism

for the clonal expansion of resistant hepatocytes and their progression to hepatocellular carcinoma (HCC). Recent studies in both Drosophila and mammals have implicated the Hippo signaling pathway as a potent regulator of organ size and tissue homeostasis.13, 14 The mammalian Hippo cascade inactivates its primary effector Yes-associated protein (YAP) by promoting its cytoplasmic localization in an S127 phosphorylation-dependent manner, whereas loss of Hippo signaling leads to nuclear accumulation and therefore increased activity of YAP, which binds to transcription factors and regulates transcription of target genes involved in cell growth, proliferation, and survival. Using a conditional YAP transgenic mouse model, it was shown that overexpression of YAP in mice leads to HCC development, suggesting a direct link between dysregulation of the Hippo size-control pathway and liver tumorigenesis.