Liver kinase B1 regulates the centrosome via PLK1

被引:0
作者
K Werle
J Chen
H-G Xu
R-X Zhao
Q He
C Lu
R Cui
J Liang
Y-L Li
Z-X Xu
机构
[1] Comprehensive Cancer Center,Division of Hematology and Oncology
[2] University of Alabama at Birmingham,Department of Dermatology
[3] Boston University School of Medicine,Department of Systems Biology
[4] UT MD Anderson Cancer Center,undefined
[5] Key Laboratory of Pathobiology,undefined
[6] Ministry of Education,undefined
[7] Norman Bethune College of Medicine,undefined
[8] Jilin University,undefined
来源
Cell Death & Disease | 2014年 / 5卷
关键词
LKB1; centrosome; genomic instability; PLK1; NUAK1;
D O I
暂无
中图分类号
学科分类号
摘要
Liver kinase B1 (LKB1) is a tumor suppressor mutationally inactivated in Peutz–Jeghers syndrome (PJS) and various sporadic cancers. Although LKB1 encodes a kinase that possesses multiple functions, no individual hypothesis posed to date has convincingly explained how loss of LKB1 contributes to carcinogenesis. In this report we demonstrated that LKB1 maintains genomic stability through the regulation of centrosome duplication. We found that LKB1 colocalized with centrosomal proteins and was situated in the mitotic spindle pole. LKB1 deficiency-induced centrosome amplification was independent of AMP-activated protein kinase (AMPK), a well-defined substrate of LKB1. Cells lacking LKB1 exhibited an increase in phosphorylated and total Polo-like kinase 1 (PLK-1), NIMA-related kinase 2 (NEK2), and ninein-like protein (NLP). Overexpression of active PLK1 (T210D) reversed the inhibition of LKB1 on centrosome amplification. In contrast, depletion of PLK1 with siRNA or suppression of PLK1 kinase activity with BTO-1 (5-Cyano-7-nitro-2-benzothiazolecarboxamide-3-oxide) abrogated LKB1 deficiency-induced centrosome amplification. We further characterized that LKB1 phosphorylated and activated AMPK-related kinase 5 (NUAK1 or ARK5) that in turn increased the phosphorylation of MYPT1, enhanced the binding between MYPT1–PP1 and PLK1, and conferred an effective dephosphorylation of PLK1. More importantly, we noted that LKB1-deficient cells exhibited multiple nuclear abnormalities, such as mitotic delay, binuclear, polylobed, grape, large, and micronuclear. Immediate depletion of LKB1 resulted in the accumulation of multiploidy cells. Expression of LKB1 is reversely correlated with the levels of PLK1 in human cancer tissues. Thus, we have uncovered a novel function of LKB1 in the maintenance of genomic stability through the regulation of centrosome mediated by PLK1.
引用
收藏
页码:e1157 / e1157
相关论文
共 243 条
[1]  
Alessi DR(2006)LKB1-dependent signaling pathways Annu Rev Biochem 75 137-163
[2]  
Sakamoto K(1998)A serine/threonine kinase gene defective in Peutz-Jeghers syndrome Nature 391 184-187
[3]  
Bayascas JR(2002)Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation Nature 419 162-167
[4]  
Hemminki A(2010)Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors Cancer Cell 17 547-559
[5]  
Markie D(2010)Homozygous deletion of the STK11/LKB1 locus and the generation of novel fusion transcripts in cervical cancer cells Cancer Genet Cytogenet 197 130-141
[6]  
Tomlinson I(2004)Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD Cell 116 457-466
[7]  
Avizienyte E(2010)Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells Nature 468 701-704
[8]  
Roth S(2007)The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis Nat Cell Biol 9 218-224
[9]  
Loukola A(2006)5'-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments Mol Cell Biol 26 5336-5347
[10]  
Bardeesy N(2004)The LKB1 tumor suppressor negatively regulates mTOR signaling Cancer Cell 6 91-99