상근피의 Hippo 신호전달 경로 활성화를 통한 YAP 억제 효능
Root Bark of Morus Alba Suppresses the YAP Activity through Activation of Classical Hippo Signaling Pathway
4
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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 μg/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.
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 μg/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.
참고문헌 (38)
- Pan D, "The hippo signaling pathway in development and cancer", Developmental cell, 19(4), pp.491~505 (2010)
- Harvey KF, "The Hippo pathway and human cancer", Nat Rev Cancer, 13(4), pp.246~257 (2013)
- Zhao B, "The Hippo-YAP pathway in organ size control and tumorigenesis : an updated version", Genes & development, 24(9), pp.862~874 (2010)
- Mo JS, "The Hippo signaling pathway in stem cell biology and cancer", EMBO reports, 15(6), pp.642~656 (2014)
- Moroishi T, "The emerging roles of YAP and TAZ in cancer", Nat Rev Cancer, 15(2), pp.73~79 (2015)
- Yimlamai D, "Hippo pathway activity influences liver cell fate", Cell, 157(6), pp.1324~1338 (2014)
- Xin M, "Hippo pathway effector Yap promotes cardiac regeneration", Proceedings of the National Academy of Sciences of the United States of America, 110(34), pp.13839~13844 (2013)
- Graves JD, "Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1", Embo J, 17(8), pp.2224~2234 (1998)
- Lee KK, "Phosphorylation and dimerization regulate nucleocytoplasmic shuttling of mammalian STE20-like kinase(MST)", The Journal of biological chemistry, 277(14), pp.12351~12358 (2002)
- Piccolo S, "The biology of YAP", TAZ : hippo signaling and beyond, 2014, pp.94(4), 1287~1312
- Zhao B, "Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control", Genes & development, 21(21), pp.2747~2761 (2007)
- Yu FX, "The Hippo pathway : regulators and regulations", Genes & development, 27(4), pp.355~371 (2013)
- 모정순, "The role of extracellular biophysical cues in modulating the Hippo-YAP pathway", BMB Reports, 50(2), pp.71~78 (2017), 생화학분자생물학회
- Heo, J, "Dongeuibogam", pp.2010~ (2007), Bupin publish co
- Yang Y, "The latest review on the polyphenols and their bioactivities of Chinese Morus plants", Journal of Asian Natural Products Research, 16(6), pp.690~702 (2014)
- Lim HJ, "The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation", Journal of ethnopharmacology, 149(1), pp.169~175 (2013)
- Wu YX, "Anti-inflammatory effects of mulberry (Morus alba L.) root bark and its active compounds", Nat Prod Res, pp.1~4 (2018)
- Chang LW, "Antioxidant and antityrosinase activity of mulberry (Morus alba L.) twigs and root bark", Food Chem Toxicol, 49(4), pp.785~790 (2011)
- Eo HJ, "Anti-inflammatory and anti-cancer activity of mulberry (Morus alba L.) root bark", BMC complementary and alternative medicine, 14, pp.200~ (2014)
- Kikuchi T, "Albanol A from the root bark of Morus alba L. induces apoptotic cell death in HL60 human leukemia cell line", Chem Pharm Bull(Tokyo), 58(4), pp.568~571 (2010)
- Yu FX, "Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling", Cell, 150(4), pp.780~791 (2012)
- Mo JS, "Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway", Nat Cell Biol, 17(4), pp.500~510 (2015)
- Zhao B, "The Hippo-YAP pathway : new connections between regulation of organ size and cancer", Curr Opin Cell Biol, 20(6), pp.638~646 (2008)
- Kango-Singh M, "Regulation of Organ Size : Insights From the Drosophila Hippo Signaling Pathway", Dev Dynam, 238(7), pp.1627~1637 (2009)
- Hao YW, "Tumor suppressor LATS1 is a negative regulator of oncogene YAP", Journal of Biological Chemistry, 283(9), pp.5496~5509 (2008)
- Camargo FD, "YAP1 increases organ size and expands undifferentiated progenitor cells", Current Biology, 17(23), pp.2054~2060
- Dong J, "Elucidation of a universal size-control mechanism in Drosophila and mammals", Cell, 130(6), pp.1120~1133 (2007)
- Johnson R, "The two faces of Hippo : targeting the Hippo pathway for regenerative medicine and cancer treatment", Nature reviews Drug discovery, 13(1), pp.63~79 (2014)
- Hong JH, "TAZ, a transcriptional modulator of mesenchymal stem cell differentiation", Science, 309(5737), pp.1074~1078 (2005)
- Cordenonsi M, "The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells", Cell, 147(4), pp.759~772 (2011)
- Chan SW, "A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells", Cancer Res, 68(8), pp.2592~2598 (2008)
- Basu-Roy U, "Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells", Nature communications, 6, pp.6411~ (2015)
- Bartucci M, "TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells", Oncogene, 34(6), pp.681~690 (2015)
- Zhao B, "Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis", Genes & development, 26(1), pp.54~68 (2012)
- Shackelford DB, "The LKB1-AMPK pathway : metabolism and growth control in tumour suppression", Nat Rev Cancer, 9(8), pp.563~575 (2009)
- Wang W, "AMPK modulates Hippo pathway activity to regulate energy homeostasis", Nat Cell Biol, 17(4), pp.490~499 (2015)
- Zhao B, "A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF beta-TRCP", Genes & development, 24(1), pp.72~85 (2010)
- Zhao B, "TEAD mediates YAP-dependent gene induction and growth control", Genes & development, 22(14), pp.1962~1971 (2008)