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Deubiquitinase YOD1: the potent activator of YAP in hepatomegaly and liver cancer
( Youngeun Kim ),( Eek-hoon Jho ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.6
Advances in the understanding of the Hippo signaling as a key regulatory pathway of proliferation and apoptosis have provided mechanical insights for controlling organ size and tumorigenicity. Recently, much attention has been directed to the regulation of LATS1/2 (large tumor suppressor) kinases that phosphorylate YAP/TAZ, a transcriptional co-activator in the Hippo pathway, and control the level and nuclear localization of YAP/TAZ. In our recent work, we showed that deubi-quitinase YOD1 stabilizes ITCH, and facilitates ITCH-mediated LATS1/2 ubiquitination and degradation, resulting in increased YAP/TAZ level. Furthermore, we found that the YOD1- ITCH-LATS1/2-YAP/TAZ signaling axis is controlled by the differential expression of miR-21 in a cell-density-dependent manner. Using a transgenic mouse model, we showed that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, a strong correlation was observed between YOD1 and YAP expression in liver cancer patients. Overall, our data suggest that YOD1 is a novel regulator of the Hippo pathway, and thereby a potential therapeutic target for liver cancer. [BMB Reports 2017; 50(6): 281-282]
The history and regulatory mechanism of the Hippo pathway
( Wantae Kim ),( Eek-hoon Jho ) 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.3
How the organ size is adjusted to the proper size during development and how organs know that they reach the original size during regeneration remain long-standing questions. Based on studies using multiple model organisms and approaches for over 20 years, a consensus has been established that the Hippo pathway plays crucial roles in controlling organ size and maintaining tissue homeostasis. Given the significance of these processes, the dysregulation of the Hippo pathway has also implicated various diseases, such as tissue degeneration and cancer. By regulating the downstream transcriptional coactivators YAP and TAZ, the Hippo pathway coordinates cell proliferation and apoptosis in response to a variety of signals including cell contact inhibition, polarity, mechanical sensation and soluble factors. Since the core components and their functions of the Hippo pathway are evolutionarily conserved, this pathway serves as a global regulator of organ size control. Therefore, further investigation of the regulatory mechanisms will provide physiological insights to better understand tissue homeostasis. In this review, the historical developments and current understandings of the regulatory mechanism of Hippo signaling pathway are discussed. [BMB Reports 2018; 51(3): 106-118]
Protein arginine methyltransferases (PRMTs) as therapeutic targets
Cha, Boksik,Jho, Eek-Hoon Informa UK, Ltd. 2012 Expert opinion on therapeutic targets Vol.16 No.7
<P><B><I>Introduction:</I></B> Protein arginine methyltransferases (PRMTs) add one or two monomethyl groups to the guanidino nitrogen atoms of arginine residues, resulting in epigenetic modification of histones or changes of protein-protein interactions, which in turn leads to the regulation of a variety of biological functions, including transcriptional activation/repression, signal transduction, cell differentiation, and embryonic development. As dysregulation of PRMTs has been observed in diverse types of cancers and modulation of their levels affects cancer cell growth, these enzymes are considered to be potential therapeutic targets.</P><P><B><I>Areas covered:</I></B> In this review, we examined recent advances in our understanding of the regulatory mechanisms of PRMT activity and the biological roles of PRMTs in embryonic stem cell, Wnt/β-catenin signaling, and cancer development.</P><P><B><I>Expert opinion:</I></B> The roles of PRMTs have been fairly well established, but further studies are required to determine how PRMTs are regulated by cellular signaling pathways <I>in vivo.</I> Since the usage of adult stem cells is under intense scrutiny by society, identification of the roles of PRMTs in adult stem cells is expected in the near future. Although small molecules specific to PRMTs with high potency <I>in vitro</I> have been identified, development of small molecules that can regulate the activity of PRMTs <I>in vivo</I> is urgently required for therapeutic purposes.</P>