Browse > Article
http://dx.doi.org/10.15188/kjopp.2019.08.33.4.191

Root Bark of Morus Alba Suppresses the YAP Activity through Activation of Classical Hippo Signaling Pathway  

Cho, You Na (School of Korean Medicine, Division of Applied Medicine, Pusan National University)
Choi, Da Bin (School of Korean Medicine, Division of Applied Medicine, Pusan National University)
Jeong, Han Sol (School of Korean Medicine, Division of Applied Medicine, Pusan National University)
Publication Information
Journal of Physiology & Pathology in Korean Medicine / v.33, no.4, 2019 , pp. 191-197 More about this Journal
Abstract
This study aims to evaluate the effects of the root bark of Morus alba (RMA) on the regulation of the Hippo-YAP pathway. Hippo-YAP signaling is a critical regulator in controlling organ size and tissue homeostasis. Hippo, the serine/threonine kinase phosphorylate the LATS. Phosphorylated LATS then phosphorylates and inactivates the YAP and TAZ, which are two closely related transcriptional co-activator. Here we report RMA activates the Hippo signaling, thereby inhibits the YAP/TAZ activity. First, we examine the cytotoxic effects of RMA by MTT assay. RMA was cytotoxic at concentrations higher than $50{\mu}g/ml$ in HEK293A cells. The reporter gene assay was performed to measure the activity of TEAD, a key transcription factor that controls cell growth and proliferation. RMA significantly suppressed the luciferase activity. By phos-taq gel shift assay, and western blotting, we showed that RMA enhanced the phosphorylation of YAP in wild type cells, but not in LATS1/2 knock out cells, which means RMA activates classical Hippo pathway. RMA induced the cytoplasmic sequestration of YAP. RMA also suppressed the mRNA expression of CTGF and CYR61; the two major YAP dependent genes. Taken together, RMA is considered to be a good candidate for proliferative disease such as cancer, by facilitating cell death through activating the Hippo signaling pathway.
Keywords
Hippo-YAP; Cancer; Phos-taq; Root bark of Morus alba;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Pan D. The hippo signaling pathway in development and cancer. Developmental cell. 2010;19(4):491-505.   DOI
2 Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13(4):246-57.   DOI
3 Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes & development. 2010;24(9):862-74.   DOI
4 Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO reports. 2014;15(6):642-56.   DOI
5 Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15(2):73-9.   DOI
6 Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, et al. Hippo pathway activity influences liver cell fate. Cell. 2014;157(6):1324-38.   DOI
7 Xin M, Kim Y, Sutherland LB, Murakami M, Qi X, McAnally J, et al. Hippo pathway effector Yap promotes cardiac regeneration. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(34):13839-44.   DOI
8 Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DK, Wright M, et al. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. Embo J. 1998;17(8):2224-34.   DOI
9 Lee KK, Yonehara S. Phosphorylation and dimerization regulate nucleocytoplasmic shuttling of mammalian STE20-like kinase (MST). The Journal of biological chemistry. 2002;277(14):12351-8.   DOI
10 Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond. Physiological reviews. 2014;94(4):1287-312.   DOI
11 Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes & development. 2007;21(21):2747-61.   DOI
12 Yu FX, Guan KL. The Hippo pathway: regulators and regulations. Genes & development. 2013;27(4):355-71.   DOI
13 Mo JS. The role of extracellular biophysical cues in modulating the Hippo-YAP pathway. Bmb Rep. 2017;50(2):71-8.   DOI
14 Heo, J, Dongeuibogam. Seoul: Bupin publish co. p 2010:2007.
15 Chang LW, Juang LJ, Wang BS, Wang MY, Tai HM, Hung WJ, et al. Antioxidant and antityrosinase activity of mulberry (Morus alba L.) twigs and root bark. Food Chem Toxicol. 2011;49(4):785-90.   DOI
16 Yang Y, Tan YX, Chen RY, Kang J. The latest review on the polyphenols and their bioactivities of Chinese Morus plants. Journal of Asian Natural Products Research. 2014;16(6):690-702.   DOI
17 Lim HJ, Jin HG, Woo ER, Lee SK, Kim HP. The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation. Journal of ethnopharmacology. 2013;149(1):169-75.   DOI
18 Wu YX, Kim YJ, Kwon TH, Tan CP, Son KH, Kim T. Anti-inflammatory effects of mulberry (Morus alba L.) root bark and its active compounds. Nat Prod Res. 2018:1-4.   DOI
19 Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 2012;150(4):780-91.   DOI
20 Kikuchi T, Nihei M, Nagai H, Fukushi H, Tabata K, Suzuki T, et al. Albanol A from the root bark of Morus alba L. induces apoptotic cell death in HL60 human leukemia cell line. Chem Pharm Bull (Tokyo). 2010;58(4):568-71.   DOI
21 Hao YW, Chun A, Cheung K, Rashidi B, Yang XL. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. Journal of Biological Chemistry. 2008;283(9):5496-509.   DOI
22 Mo JS, Meng Z, Kim YC, Park HW, Hansen CG, Kim S, et al. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat Cell Biol. 2015;17(4):500-10.   DOI
23 Zhao B, Lei QY, Guan KL. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol. 2008;20(6):638-46.   DOI
24 Kango-Singh M, Singh A. Regulation of Organ Size: Insights From the Drosophila Hippo Signaling Pathway. Dev Dynam. 2009;238(7):1627-37.   DOI
25 Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Current Biology. 17(23):2054-60.   DOI
26 Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130(6):1120-33.   DOI
27 Eo HJ, Park JH, Park GH, Lee MH, Lee JR, Koo JS, et al. Anti-inflammatory and anti-cancer activity of mulberry (Morus alba L.) root bark. BMC complementary and alternative medicine. 2014;14:200.   DOI
28 Johnson R, Halder G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nature reviews Drug discovery. 2014;13(1):63-79.   DOI
29 Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science. 2005;309(5737):1074-8.   DOI
30 Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147(4):759-72.   DOI
31 Chan SW, Lim CJ, Guo K, Ng CP, Lee I, Hunziker W, et al. A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. Cancer Res. 2008;68(8):2592-8.   DOI
32 Basu-Roy U, Bayin NS, Rattanakorn K, Han E, Placantonakis DG, Mansukhani A, et al. Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells. Nature communications. 2015;6:6411.   DOI
33 Bartucci M, Dattilo R, Moriconi C, Pagliuca A, Mottolese M, Federici G, et al. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene. 2015;34(6):681-90.   DOI
34 Zhao B, Li L, Wang L, Wang CY, Yu J, Guan KL. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes & development. 2012;26(1):54-68.   DOI
35 Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9(8):563-75.   DOI
36 Wang W, Xiao ZD, Li X, Aziz KE, Gan B, Johnson RL, et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat Cell Biol. 2015;17(4):490-9.   DOI
37 Zhao B, Li L, Tumaneng K, Wang CY, Guan KL. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF beta-TRCP. Genes & development. 2010;24(1):72-85.   DOI
38 Zhao B, Ye X, Yu J, Li L, Li W, Li S, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes & development. 2008;22(14):1962-71.   DOI