title: Constitutive ERK1/2 activation contributes to production of double minute chromosomes in tumour cells.
abstract: 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.
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, People's Republic of China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Sun
authors.forename: Chao
authors.initials: C
authors.lastname: Quan
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Ji
authors.forename: Lisa
authors.initials: L
authors.lastname: Yu
authors.forename: Xinxin
authors.initials: X
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Zheng
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zou
authors.forename: Quanxiao
authors.initials: Q
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Yunyan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yunfu
authors.initials: Y
authors.lastname: Cui
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Jia
authors.forename: Xiangning
authors.initials: X
authors.lastname: Meng
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.forename: Jingcui
authors.initials: J
authors.lastname: Yu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics*; D004789:Enzyme Activation; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ERK1/2 constitutive phosphorylation; MAPK signalling pathway; double minute chromosomes; malignant tumour