综述

哺乳动物Hippo信号通路:肿瘤治疗的新标靶

展开
  • 南昌大学基础医学院生物化学与分子生物学教研室, 南昌 330006

收稿日期: 2011-08-02

  修回日期: 2011-09-23

  网络出版日期: 2012-03-25

基金资助

江西省自然科学基金项目(编号:2010JZY0237)资助

Hippo signaling pathway in mammals:a new therapeutic target for tumors

Expand
  • Department of Biochemistry and Molecular Biology, Basic Medical College of Nanchang University, Nanchang 330006, China

Received date: 2011-08-02

  Revised date: 2011-09-23

  Online published: 2012-03-25

摘要

Hippo信号通路是首次在果蝇中发现具有调节细胞增殖与凋亡作用的信号通路。最近发现果蝇Hippo信号通路的组成、分子作用机制和生物学功能在进化过程中高度保守。Hippo信号通路在胚胎发育中对细胞的生长分化、组织器官形成以及成体干细胞的维持和自稳态的保持等方面具有重要作用。同时, Hippo信号通路与Wnt信号通路、Notch信号通路等相互作用、密切联系, 在肿瘤的发生、发展过程中也起到关键作用。文章综述了哺乳动物Hippo信号通路的作用机理、与其他信号通路和蛋白质因子的相互联系及与肿瘤的关系, 对于肿瘤的诊断、预防和治疗具有一定的参考价值。

本文引用格式

许传铭,万福生 . 哺乳动物Hippo信号通路:肿瘤治疗的新标靶[J]. 遗传, 2012 , 34(3) : 269 -280 . DOI: 10.3724/SP.J.1005.2012.00269

Abstract

Hippo signaling pathway was first discovered in Drosophila as regulator of cell proliferation and apoptosis during development. It has been widely reported that Hippo signaling pathway plays an essential role in embryonic differentiation, pattern formation and adult cell homeostasis. Furthermore, Hippo signaling has close correlation with Wnt and Notch signaling pathways, and has an important effect on tumor initiation and progression. Recent studies have shown that the Drosophila Hippo signaling pathway is highly conserved over evolutionary time, the mammalian Hippo signaling pathway has been implicated in regulating cell contact inhibition, organsize and tumorigenesis. This review firstly focuses on the composition, regulatory mechanism and physiological functions of mammalian Hippo signaling pathway, and then lists the relationship with other signaling pathways and protein factors, and tumors in mammals. Finally, the therapeutic approaches to targeting Hippo signaling pathway components or regulators have also been summarized, which might be beneficial to tumor therapeutic intervention.

参考文献

[1] Huang JB, Wu S, Barrera J, Matthews K, Pan DJ. The Hippo signaling pathway coordinately regulates cell pro-liferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell, 2005, 122(3): 421-434.
[2] Halder G, Johnson RL. Hippo signaling: growth control and beyond. Development, 2011, 138(1): 9-22.
[3] Dong JX, Feldmann G, Huang JB, Wu S, Zhang NL, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan DJ. Elucidation of a universal size control mechanism in Drosophila and mammals. Cell, 2007, 130(6): 1120-1133.
[4] Liu AM, Xu MZ, Chen JF, Poon RT, Luk JM. Targeting YAP and Hippo signaling pathway in liver cancer. Expert Opin Ther Targets, 2010, 14(8): 855-868.
[5] Zhao B, Li L, Lei QY, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev, 2010, 24(9): 862-874.
[6] Mao YP, Mulvaney J, Zakaria S, Yu T, Morgan KM, Allen S, Basson MA, Francis-West P, Irvine KD. Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development. Development, 2011, 138(5): 947-957.
[7] Angus L, Moleirinho S, Herron L, Sinha A, Zhang X, Niestrata M, Dholakia K, Prystowsky MB, Harvey KF, Reynolds PA, Gunn-Moore FJ. Willin/FRMD6 expression activates the Hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP. Oncogene, 2011, 31(2): 238-250.
[8] Zhang NL, Bai HB, David KK, Dong JX, Zheng YG, Cai J, Giovannini M, Liu PT, Anders RA, Pan DJ. The Merlin/NF2 tumor suppressor functions through the YAP on-coprotein to regulate tissue homeostasis in mammals. Dev Cell, 2010, 19(1): 27-38.
[9] Xiao L, Chen YH, Ji M, Dong JX. KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases. J Biol Chem, 2011, 286(10): 7788-7796.
[10] Song H, Mak KK, Topol L, Yun KS, Hu JX, Garrett L, Chen YB, Park O, Chang J, Simpson RM, Wang CY, Gao B, Jiang J, Yang YZ. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci USA, 2010, 107(4): 1431-1436.
[11] Luo XL, Hu JB, Li ZM, Yan Q, Li XL, Tao DD, Wang J, Leng Y, Gardner K, Judge SIV, Li QQ, Gong JP. The human WW45 protein enhances MST1-mediated apoptosis in vivo. Int J Mol Med, 2009, 23(3): 357-362.
[12] Hergovich A, Schmitz D, Hemmings BA. The human tumour suppressor LATS1 is activated by human MOB1 at the membrane. Biochem Biophys Res Commun, 2006, 345(1): 50-58.
[13] Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, Mu D, Lucito R, Powers S, Lowe SW. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell, 2006; 125(7): 1253-1267.
[14] Morin-Kensicki EM, Boone BN, Howell M, Stonebraker JR, Teed J, Alb JG, Magnuson TR, O'Neal W, Milgram SL. Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted dis-ruption of Yap65. Mol Cell Biol, 2006, 26(1): 77-87.
[15] Makita R, Uchijima Y, Nishiyama K, Amano T, Chen Q, Takeuchi T, Mitani A, Nagase T, Yatomi Y, Aburatani H, Nakagawa O, Small EV, Cobo-Stark P, Igarashi P, Murakami M, Tominaga J, Sato T, Asano T, Kurihara Y, Kurihara H. Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ. Am J Physiol Renal Physiol, 2008, 294(3): F542-F553.
[16] Zhao B, Ye X, Yu JD, Li L, Li WQ, Li SM, Yu JJ, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev, 2008, 22(14): 1962-1971.
[17] Zhang H, Liu CY, Zha ZY, Zhao B, Yao J, Zhao S, Xiong Y, Lei QY, Guan KL. TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesen- chymal transition.
文章导航

/