磷酸酶Wip1基因敲除表型及机制研究进展

doi:10.11843/j.issn.0366-6964.2017.12.002

摘要/Abstract

摘要：

野生型p53诱导的磷酸酶1（Wild-type p53-induced phosphatase1，Wip1）是PP2C（The type 2C family of protein phosphatases）磷酸酶家族中的一员。在DNA损伤修复中起重要作用，并作为原癌基因受到越来越多的关注。Wip1敲除小鼠虽然能够存活，但寿命缩短，并出现多系统异常，包括生殖系统、免疫体系、内分泌系统、神经系统等，具体表现：雄性生殖器官萎缩及雄性不育、对病原体敏感、T细胞和B细胞功能受损、胰岛素抵抗、体重增长受限、脂肪量减少、焦虑和抑郁样行为增加等。相关机制研究发现，Wip1通过去磷酸化不同蛋白底物而在多种生理和病理过程中发挥重要作用。本文旨在对小鼠Wip1基因缺失所致表型及其初步的分子机制进行综述，为进一步研究Wip1的生物学功能以及哺乳动物体内生理和病理过程的发生机制提供参考。

Abstract:

Wip1 (Wild-type p53-induced phosphatase1) is a member of PP2C (The type 2C family of protein phosphatases) family of phosphatases, which plays important roles in DNA damage repair and has attracted increasing attention as a oncogene. Wip1 knockout mice were viable, but exhibited reduced longevity, along with multiple-system abnormalities, including reproductive system, immune system, endocrine system and nervous system. The detailed phenotypes included male reproductive organ atrophy, male infertility, increased susceptibility to pathogens, diminished T-and B-cell function, insulin resistance, impaired body weight, declined fat mass,elevated anxiety-and depression-like behaviors and so on. The studies for the underlying molecular mechanisms further demonstrated that Wip1 played critical roles in a variety of physiological and pathological processes through dephosphorylating different substrate proteins. Therefore, in this review, we comprehensively discussed the phenotypes caused by Wip1 knockout in mouse as well as the possible underlying molecular mechanisms, which may provide information for further understanding the biological function of Wip1, and the possible mechanisms underlying the physiological and pathological processes in mammals.

中图分类号:

王冰源, 刘志国, 牟玉莲. 磷酸酶Wip1基因敲除表型及机制研究进展[J]. 畜牧兽医学报, 2017, 48(12): 2232-2238.

WANG Bing-yuan, LIU Zhi-guo, MU Yu-lian. Research Progress of Wip1 Phosphatase Knockout Phenotypes and Underlying Mechanisms[J]. ACTA VETERINARIA ET ZOOTECHNICA SINICA, 2017, 48(12): 2232-2238.

参考文献

[1] FISCELLA M, ZHANG H L, FAN S J, et al. Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner[J]. Proc Natl Acad Sci U S A, 1997, 94(12):6048-6053.
[2] BRAZINA J, SVADLENKA J, MACUREK L, et al. DNA damage-induced regulatory interplay between DAXX, p53, ATM kinase and Wip1 phosphatase[J]. Cell Cycle, 2015, 14(3):375-387.
[3] LU X B, NGUYEN T A, DONEHOWER L A. Reversal of the ATM/ATR-mediated DNA damage response by the oncogenic phosphatase PPM1D[J]. Cell Cycle, 2005, 4(8):4060-4064.
[4] WANG H Y, LIU Z S, QIU L, et al. Knockdown of Wip1 enhances sensitivity to radiation in hela cells through activation of p38 MAPK[J]. Oncol Res, 2014, 22(4):225-233.
[5] CHA H, LOWE J M, LI H H, et al. Wip1 directly dephosphorylates γ-H2AX and attenuates the DNA damage response[J]. Cancer Res, 2010, 70(10):4112-4122.
[6] WANG Z P, CHEN S Y, TIAN Y. Wild-type p53-induced phosphatase 1 is a prognostic marker and therapeutic target in bladder transitional cell carcinoma[J]. Oncol Lett, 2017, 13(2):875-880.
[7] CHEN Z H, WANG L, YAO D Y, et al. Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis[J]. Sci Rep, 2016, 6:38011.
[8] ELSHAMY W M. Induction of breast cancer in wild type p53 cells by BRCA1-IRIS overexpression[J]. Hawaii Med J, 2010, 69(8):200-201.
[9] WANG B, LI D P, SIDLER C, et al. A suppressive role of ionizing radiation-responsive miR-29c in the development of liver carcinoma via targeting WIP1[J]. Oncotarget, 2015, 6(12):9937-9950.
[10] ZHANG Y Q, SUN H, HE G X, et al. WIP1 regulates the proliferation and invasion of nasopharyngeal carcinoma in vitro[J]. Tumour Biol, 2014, 35(8):7651-7657.
[11] FUKU T, SEMBA S, YUTORI H, et al. Increased wild-type p53-induced phosphatase 1(Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma[J]. Pathol Int, 2007, 57(9):566-571.
[12] CHOI J, NANNENGA B, DEMIDOV O N, et al. Mice deficient for the wild-type p53-induced phosphatase gene (Wip1) exhibit defects in reproductive organs, immune function, and cell cycle control[J]. Mol Cell Biol, 2002, 22(4):1094-1105.
[13] SUN B, HU X L, LIU G W, et al. Phosphatase Wip1 negatively regulates neutrophil migration and inflammation[J]. J Immunol, 2014, 192(3):1184-1195.
[14] YI W W, HU X L, CHEN Z Y, et al. Phosphatase Wip1 controls antigen-independent B-cell development in a p53-dependent manner[J]. Blood, 2015, 126(5):620-628.
[15] CHEN Z Y, YI W W, MORITA Y, et al. Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways[J]. Nat Commun, 2015, 6:6808.
[16] JEONG H C, GIL N Y, LEE H S, et al. Timely degradation of Wip1 phosphatase by APC/C activator protein Cdh1 is necessary for normal mitotic progression[J]. J Cell Biochem, 2015, 116(8):1602-1612.
[17] LE GUEZENNEC X, BRICHKINA A, HUANG Y F, et al. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis[J]. Cell Metab, 2012, 16(1):68-80.
[18] SAKAI H, FUJIGAKI H, MAZUR S J, et al. Wild-type p53-induced phosphatase 1(Wip1) forestalls cellular premature senescence at physiological oxygen levels by regulating DNA damage response signaling during DNA replication[J]. Cell Cycle, 2014, 13(6):1015-1029.
[19] ZHU Y H, DEMIDOV O N, GOH A M, et al. Phosphatase Wip1 regulates adult neurogenesis and WNT signaling during aging[J]. J Clin Invest, 2014, 124(7):3263-3273.
[20] ZHANG L L, LIU L M, HE Z Y, et al. Inhibition of wild-type p53-induced phosphatase 1 promotes liver regeneration in mice by direct activation of mammalian target of rapamycin[J]. Hepatology, 2015, 61(6):2030-2041.
[21] FILIPPONI D, MULLER J, EMELYANOV A, et al. Wip1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation[J]. Cancer Cell, 2013, 24(4):528-541.
[22] SHREERAM S, DEMIDOV O N, HEE W K, et al. Wip1 phosphatase modulates ATM-dependent signaling pathways[J]. Mol Cell, 2006, 23(5):757-764.
[23] CHO S J, CHA B S, KWON O S, et al. Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development[J]. Biochim Biophys Acta-Mol Basis Dis, 2017, 1863(4):1013-1022.
[24] CASTRILLON D H, QUADE B J, WANG T Y, et al. The human VASA gene is specifically expressed in the germ cell lineage[J]. Proc Natl Acad Sci U S A, 2000, 97(17):9585-9590.
[25] TSUDA M, SASAOKA Y, KISO M, et al. Conserved role of nanos proteins in germ cell development[J]. Science, 2003, 301(5637):1239-1241.
[26] YOUNGREN K K, COVENEY D, PENG X N, et al. The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours[J]. Nature, 2005, 435(7040):360-364.
[27] IRIE N, WEINBERGER L, TANG W W C, et al. SOX17 is a critical specifier of human primordial germ cell fate[J]. Cell, 2015, 160(1-2):253-268.
[28] SUZUKI H, TSUDA M, KISO M, et al. Nanos3 maintains the germ cell lineage in the mouse by suppressing both Bax-dependent and-independent apoptotic pathways[J]. Dev Biol, 2008, 318(1):133-142.
[29] ENGERT S, BURTSCHER I, LIAO W P, et al. Wnt/β-catenin signalling regulates Sox17 expression and is essential for organizer and endoderm formation in the mouse[J]. Development, 2013, 140(15):3128-3138.
[30] YANG S H, ANDL T, GRACHTCHOUK V, et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/β-catenin signaling[J]. Nat Genet, 2008, 40(9):1130-1135.
[31] SCHITO M L, DEMIDOV O N, SAITO S, et al. Wip1 phosphatase-deficient mice exhibit defective T cell maturation due to sustained p53 activation[J]. J Immunol, 2006, 176(8):4818-4825.
[32] SUN L N, LI H R, LUO H Y, et al. Phosphatase Wip1 is essential for the maturation and homeostasis of medullary thymic epithelial cells in mice[J]. J Immunol, 2013, 191(6):3210-3220.
[33] WONG E S M, LE GUEZENNEC X, DEMIDOV O N, et al. p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age[J]. Dev Cell, 2009, 17(1):142-149.
[34] ARMATA H L, CHAMBERLAND S, WATTS L, et al. Deficiency of the tumor promoter gene Wip1 induces insulin resistance[J]. Mol Endocrinol, 2015, 29(1):28-39.
[35] LI D H, ZHANG L J, XU L, et al. WIP1 phosphatase is a critical regulator of adipogenesis through dephosphorylating PPARγ serine 112[J]. Cell Mol Life Sci, 2017, 74(11):2067-2079.
[36] LEFTEROVA M I, HAAKONSSON A K, LAZAR M A, et al. PPARγ and the global map of adipogenesis and beyond[J]. Trends Endocrinol Metab, 2014, 25(6):293-302.
[37] HU E D, KIM J B, SARRAF P, et al. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARγ[J]. Science, 1996, 274(5295):2100-2103.
[38] ZHU Y H, ZHANG C W, LU L, et al. Wip1 regulates the generation of new neural cells in the adult olfactory bulb through p53-dependent cell cycle control[J]. Stem Cells, 2009, 27(6):1433-1442.
[39] FERNANDEZ F, SOON I, LI Z, et al. Wip1 phosphatase positively modulates dendritic spine morphology and memory processes through the p38 MAPK signaling pathway[J]. Cell Adh Migr, 2012, 6(4):333-343.
[40] RUAN C S, ZHOU F H, HE Z Y, et al. Mice deficient for wild-type p53-induced phosphatase 1 display elevated anxiety-and depression-like behaviors[J]. Neuroscience, 2015, 293:12-22.
[41] HE Z Y, WANG W Y, HU W Y, et al. Gamma-H2AX upregulation caused by Wip1 deficiency increases depression-related cellular senescence in hippocampus[J]. Sci Rep, 2016, 6:34558.