Constitutive ERK1/2 activation contributes to production of double minute chromosomes in tumour cells

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• 作者：Wenjing Sun ; Chao Quan ; Yun Huang ; Wei Ji ; Lisa Yu ; Xinxin Li ; Yang Zhang ; Zhibo Zheng ; Hongyan Zou ; Quanxiao Li ; Ping Xu ; Yan Feng ; Li Li ; Yunyan Zhang ; Yunfu Cui ; Xueyuan Jia ; Xiangning Meng ; Chunyu Zhang ; Yan Jin ; Jing Bai ; Jingcui Yu ; Yang Yu ; Jianhua Yang and Songbin Fu
• 关键词：double minute chromosomes ; malignant tumour ; MAPK signalling pathway ; ERK1/2 constitutive phosphorylation
• 刊名：The Journal of Pathology
• 出版年：2015
• 出版时间：January 2015
• 年：2015
• 卷：235
• 期：1
• 页码：14-24
• 全文大小：2654K
• ISSN：1096-9896

文摘

Double minute chromosomes (DMs) are extrachromosomal cytogenetic structures found in tumour cells. As hallmarks of gene amplification, DMs often carry oncogenes and drug-resistance genes and play important roles in malignant tumour progression and drug resistance. The mitogen-activated protein kinase (MAPK) signalling pathway is frequently dysregulated in human malignant tumours, which induces genomic instability, but it remains unclear whether a close relationship exists between MAPK signalling and DMs. In the present study, we focused on three major components of MAPK signalling, ERK1/2, JNK1/2/3 and p38, to investigate the relationship between MAPK and DM production in tumour cells. We found that the constitutive phosphorylation of ERK1/2, but not JNK1/2/3 and p38, was closely associated with DMs in tumour cells. Inhibition of ERK1/2 activation in DM-containing and ERK1/2 constitutively phosphorylated tumour cells was able to markedly decrease the number of DMs, as well as the degree of amplification and expression of DM-carried genes. The mechanism was found to be an increasing tendency of DM DNA to break, become enveloped into micronuclei (MNs) and excluded from the tumour cells during the S/G₂ phases of the cell cycle, events that accompanied the reversion of malignant behaviour. Our study reveals a linkage between ERK1/2 activation and DM stability in tumour cells.