Format

Send to

Choose Destination
Cell Death Dis. 2018 Mar 1;9(3):341. doi: 10.1038/s41419-018-0362-y.

Sei-1 promotes double minute chromosomes formation through activation of the PI3K/Akt/BRCA1-Abraxas pathway and induces double-strand breaks in NIH-3T3 fibroblasts.

Author information

1
Laboratory of Medical Genetics, Harbin Medical University, 150081, Harbin, China.
2
The Department of Otolaryngology, Heilongjiang provincial hospital, 150081, Harbin, China.
3
Obstetrics Department, Fourth Affliated Hospital, Harbin Medical University, 150081, Harbin, China.
4
Department of Clinical Oncology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
5
Key Laboratory of Medical Genetics, Harbin Medical University, Heilongjiang Higher Education Institutions, 150081, Harbin, China.
6
Laboratory of Medical Genetics, Harbin Medical University, 150081, Harbin, China. zhangcy@ems.hrbmu.edu.cn.

Abstract

Sei-1 is a potential oncogene that plays an important role in promoting genomic instability. Double minute chromosomes (DMs) are hallmarks of gene amplification and contribute to tumorigenesis. Defects in the DNA double-strand break (DSB) repairing pathways can lead to gene amplification. To date, the mechanisms governing the formation of DMs induced by Sei-1 are not fully understood. We established DMs induced by Sei-1 in the NIH-3T3 cell line. RNA-sequencing was used to identify key characteristics of differentially expressed genes. Metaphase spreads were used to calculate DM numbers. Immunofluorescence was employed to detect γH2AX foci. Western blot and Akt pathway inhibition experiments were performed to reveal the role of the PI3K/Akt/BRCA1-Abraxas pathway in Sei-1-induced DMs. Luciferase reporter assay was employed to explore the regulatory mechanisms between Sei-1 and BRCA1. DM formation was associated with a deficiency in DSB repair. Based on this finding, activation of the PI3K/Akt/BRCA1-Abraxas pathway was found to increase the DM population with passage in vivo, and inhibition resulted in a reduction of DMs. Apart from this, it was shown for the first time that Sei-1 could directly regulate the expression of BRCA1. Our results suggest that the PI3K/Akt/BRCA1-Abraxas pathway is responsible for the formation of DMs induced by Sei-1.

PMID:
29497033
PMCID:
PMC5832785
DOI:
10.1038/s41419-018-0362-y
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center