ECRG2 disruption leads to centrosome amplification and spindle checkpoint defects contributing chromosome instability.
Cancer cells contain an abnormal number of chromosomes (aneuploidy), which is a prevalent form of genetic instability in human cancers. Abnormal amplification of centrosomes and defects of spindle assembly checkpoint are the major causes of chromosome instability in cancer cells. Here we present biochemical evidence to suggest a role of ECRG2, a novel tumor suppressor gene, in maintaining chromosome stability. ECRG2 localized to centrosomes during interphase and kinetochores during mitosis. Further analysis revealed that ECRG2 participates in centrosome amplification in a p53-dependent manner. Depletion of ECRG2 not only destabilized p53, down-regulated p21, and increased the cyclin E/CDK2 activity, thus initiating centrosome amplification, but also abolished the ability of p53 localize to centrosomes. Overexpression of ECRG2 restored the p53-dependent suppression of centrosome duplication. Furthermore, ECRG2-depleted cells show severely disrupted spindle phenotype but fail to maintain the mitotic arrest due to minimal BUBR1 protein levels. Taken together, our results indicate that ECRG2 is important for ensuring centrosome duplication, spindle assembly checkpoint, and accurate chromosome segregation, and its depletion may contribute to chromosome instability and aneuploidy in human cancers.
Cheng
Xiaolong
X
Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
Shen
Zheng
Z
Yang
Jianyi
J
Lu
Shih-Hsin
SH
Cui
Yongping
Y
D000782:Aneuploidy; D000818:Animals; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism* / Q000473:pathology; D043171:Chromosomal Instability / Q000235:genetics; D020090:Chromosome Segregation / Q000235:genetics; D017353:Gene Deletion; D007399:Interphase / Q000235:genetics; D018386:Kinetochores / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D000074162:Serine Peptidase Inhibitors, Kazal Type; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D053491:Proteinase Inhibitory Proteins, Secretory; C473799:SPINK7 protein, human; D000074162:Serine Peptidase Inhibitors, Kazal Type; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases