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  • br Conflicts of interest br Significance p is required for

    2022-06-28


    Conflicts of interest
    Significance p53 is required for the induction of cell senescence to limit the proliferation of polyploid cells. We found that Hippo signal deficiency or Yap activation in mouse livers result in polyploid formation and polyploid cell growth. The combined loss of Hippo signals and p53 lead to greatly increased polyploidy and result in a higher incidence and earlier onset of liver tumors. We revealed that Yap induces cell polyploidy through the Skp2-mediated ubiquitin-proteasome pathway. Importantly, the deregulation of the Hippo-Yap-Skp2 axis is found in a substantial fraction of human hepatocellular carcinomas. Thus, Hippo-Yap signaling acts as an alternative polyploid checkpoint, together with p53, to synergistically restrain polyploid cell division, thus limiting the risk of genomic instability, aneuploidy, and tumorigenesis.
    Introduction Polyploidy is a state in which alvocidib possess more than two sets of homologous chromosomes. Although it is less frequently found in animals, some tissues, including the liver, have a high percentage of polyploid cells. Polyploid hepatocytes undergo ploidy reversal to specifically generate unique hepatocytes with different mixtures of chromosomes (Duncan, 2013, Gentric and Desdouets, 2014, Pandit et al., 2013). This genetic diversity may be an adaptive mechanism, serving as a means for the selection of hepatocytes most resistant to xenobiotic or nutritional injury. Gene redundancy shields polyploids from the deleterious effects of mutations (Duncan et al., 2009, Duncan et al., 2010). However, polyploid cells precede aneuploid cells that give rise to increased genomic instability and tumor progression (Davoli and de Lange, 2011, Ganem and Pellman, 2007, Gordon et al., 2012). Consistently, two-thirds partial hepatectomy (PH)-induced liver regeneration results in increased cell polyploidy and causes the normally quiescent polyploid hepatocytes to undergo cell-cycle re-entry and division, accelerating the ability of oncogenes to induce hepatocellular carcinoma (HCC) (Beer et al., 2004). Polyploid cells are normally arrested in the G1 phase of the cell cycle, thus preventing genomic instability, aneuploidy, and tumorigenesis. Thus, it is of particular interest to determine the mechanisms regulating polyploid formation and polyploid cell division. Cell polyploidy can result from cell fusion or abnormal cell division, including endoreduplication, mitotic slippage and cytokinesis failure (Pandit et al., 2013). Cytokinesis failure and mitotic slippage events have a pivotal role in establishing hepatocyte polyploidy (Celton-Morizur et al., 2009, Hsu et al., 2016, Pandit et al., 2012). Skp2 is a major cytokinetic regulator and an F box protein that targets p27 for ubiquitination and subsequent degradation to promote cell-cycle progression (Carrano et al., 1999, Nakayama et al., 2000, Nakayama et al., 2004). Skp2-null mice develop a phenotype of polyploidy and centrosome amplification in the liver (Kossatz et al., 2004, Nakayama et al., 2004, Serres et al., 2012). Elevated levels of p27 in the S and G2/M phases upon the depletion of Skp2 cause cytokinesis failure and mitotic slippage events. These phenotypes are completely rescued by the concomitant deletion of p27 (Nakayama et al., 2004). Recent studies revealed that Skp2 stability, sub-cellular localization, and activity are regulated by its phosphorylation and acetylation (Chan et al., 2012, Gao et al., 2009, Inuzuka et al., 2012, Lin et al., 2009). Skp2 expression is highly upregulated in a variety of human cancers (Calvisi et al., 2009, Lee et al., 2015, Lin et al., 2010, Wang et al., 2010, Zhao et al., 2013). These results indicate that certain signaling may be required for the regulation of Skp2 function in controlling cell polyploidy. The Hippo signaling pathway is a critical regulator of stem cell self-renewal, tissue regeneration, and organ size (Johnson and Halder, 2014, Pan, 2010, Yu et al., 2015). Central to this pathway is a kinase cascade formed by mammalian sterile20 kinases Mst1 and Mst2 (Mst1/2), a scaffolding protein Salvador/WW45 (Sav), an NDR family kinases large tumor suppressor 1 (Lats1) and Lats2, and an adaptor protein Mob1. Mst1/2 phosphorylates and activates Lats1/2-Mob1, which then phosphorylates the yes-associated protein (Yap) or WW domain-containing transcription regulator protein 1 (Taz). Phospho-Yap/Taz is either degraded or sequestered in the cytoplasm by 14-3-3 protein. When the Hippo pathway is inactivated, Yap/Taz translocates to the nucleus and forms a functional hybrid transcriptional factor with TEA domain family members to turn on pro-proliferative and pro-survival genes, enabling cell proliferation. The Hippo pathway also mediates crosstalk with other signaling pathways including the phosphoinositol-3-kinase (PI3K)-Akt pathway (Dupont et al., 2011, Heallen et al., 2011, Tumaneng et al., 2012, Yu et al., 2012). Genetic defects in this pathway in mice lead to tissue overgrowth and cancer development in multiple organs (Camargo et al., 2007, Dong et al., 2007, Zhou et al., 2009). A recent study showed that Hippo signaling is highly activated in polyploid cells (Ganem et al., 2014). p53 is normally required for the induction of cellular senescence to limit polyploid cell growth (Davoli et al., 2010, Fujiwara et al., 2005, Kurinna et al., 2013). Lats2 kinase of the Hippo signaling pathway was reported to stabilize p53 by inhibiting murine double minute 2 (Mdm2) (Aylon et al., 2006, Iida et al., 2004), which resulted in tetraploid cell-cycle arrest. Thus, polyploidy status might trigger Lats2 kinase to activate p53 to prevent polyploidy cell proliferation (Ganem et al., 2014). Interestingly, Yap overexpression dramatically increases hepatocyte polyploidy, suggesting that Yap is a downstream effector of Lats2 kinase in ploidy regulation (Ganem et al., 2014). Recent studies have shown that Yap is phosphorylated by cyclin-dependent kinase 1 (CDK1) and that this mitotic phosphorylation of Yap is required for the activation of the spindle checkpoint in immortalized epithelial cells (Yang et al., 2013, Yang et al., 2015). However, the mechanism by which Yap determines cell ploidy and chromosomal stability remains unclear. Genetic evidence in animals supporting the central role of Hippo signaling in polyploidy formation and subsequent neoplastic transformation is still largely lacking.