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  • ISRIB CTGF is an established YAP

    2022-01-14

    CTGF is an established YAP/TAZ target gene which plays a central role in tissue remodeling. Downregulation of CTGF mediates collagen loss in chronologically-aged human skin whereas persistent activation of CTGF can result in excessive deposition of collagen and fibrotic disorders [63]. The authors found that TGF-β-activated Smad proteins are the main inducers of CTGF and type I procollagen in human dermal fibroblasts. In fact, downregulation of the TGF-β/Smad/CTGF/procollagen axis was identified in fibroblasts in aged human skin compared to young human skin in vivo [63]. Interestingly, it has also been reported that YAP/TAZ modulates the TGF-β/Smad3 pathway in primary human skin fibroblasts. The authors found that YAP/TAZ depletion promotes Smad7 via activation of AP-1 transcription factor, which in turn impairs TGF-β/Smad3 signaling [64]. The proliferative myogenecity capacity of muscle stem ISRIB (MuSC) is essential to repair skeletal muscle after injury, while age-related dysfunction of MuSC can lead to fibrotic disorders and reduced recovery after injury [65]. Stearns‐Reider and colleagues studied the effect of age and substrate stiffness on YAP/TAZ in fibroblasts and its influence on MuSC fate. In aged fibroblasts compared to young fibroblasts, the authors found an affiliated increase of stiffness and nuclear translocation of YAP/TAZ, which stimulated matricellular protein secretion leading to fibrogenic conversion of MuSCs and a diminished myogenicity [66]. The key role of the Hippo pathway in ISRIB tissue repair and regeneration has been reported [67], and the intrinsic capacity to regenerate liver is well known. An interesting study by Mo and colleagues illuminated the modulation of the Hippo pathway in young and aged livers after partial hepatectomy. The authors found a modulation of the Hippo pathway and increased activity of YAP1 during liver regeneration. Aging was able to decrease hepatocyte proliferation, assayed as Ki67 and H&E, and increase pMST, pLATS and pYAP. Moreover, depletion of MTS1/2 recovered the regenerative capacity of liver in aged mice [68]. The study of regulation of MST1 in several tissues of aged mice has shown that MST1 mRNA expression in the heart, kidney, striatal and liver (only at 23–28 months) are reduced with aging. In the cortex and hippocampus MST1 mRNA expression increases initially then decreases with age. In contrast, in the spleen, an increase of MST1 mRNA expression level is observed with aging. The authors also found that MST1 is cleaved by CASP3, 6, and 7, and protein levels of MST1 and its fragments increase during the aging process [69].
    Hippo pathway signaling and link with cancer Cancer is a generic term for different types of diseases that can affect any part of the body. According to the World Health Organization, cancer is “the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs”. Cancer can be divided into three main stages: initiation, promotion and progression [8]. The Hippo pathway, which originally was identified in Drosophila has functions of tumor suppression and emerging evidence suggests that its dysregulation can drive tumorigenesis forward [70]. In this section, the connection between the Hippo pathway and different cancer stages will be reviewed.
    Hippo pathway signaling dysregulated in cancer The Hippo pathway is crucial for maintaining a programmed cell proliferation and for restricting tissue growth. Dysregulation of this pathway has been reported in a wide range of human cancers including breast, lung, colorectal and liver. However, germline and somatic mutations in the Hippo pathway are rare, suggesting that the abnormal activity of the Hippo pathway in cancers is governed by molecular events rather than by mutation of the pathway components [105]. In this section, we discuss the effect of dysregulated core components in the Hippo pathway - NF2, MST, LATS and YAP/TAZ in cancer biology.