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Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis.

Authors :
Wei TY
Hsia JY
Chiu SC
Su LJ
Juan CC
Lee YC
Chen JM
Chou HY
Huang JY
Huang HM
Yu CT
Source :
Cellular signalling [Cell Signal] 2014 Dec; Vol. 26 (12), pp. 2940-50. Date of Electronic Publication: 2014 Sep 30.
Publication Year :
2014

Abstract

Methylosome protein 50 (MEP50) is a component of methylosome where MEP50 binds protein substrates and activates the oncogenic protein arginine methyl transferase 5 (PRMT5). MEP50 is also a coactivator for androgen receptor (AR) and estrogen receptor (ER), and transforms cells in the presence of androgen or estrogen. To extend the understanding of how MEP50 transforms cells, we investigated whether MEP50 could transform cells independent of AR and ER, and clarified whether PRMT5 could contribute to the MEP50-caused tumor formation. Microarray and Western blot analyses revealed the association of MEP50 with many human cancers including lung cancer. Knockdown of MEP50 retarded cell growth and migration in selected lung cancer cell lines, which expressed very low level of AR and ER and were insensitive to inhibitors of AR and ER. Moreover, overexpression of Myc-MEP50 enhanced cell transforming activities of 293T cells which are known lack of expression of AR and ER. Mechanistic analyses showed that MEP50 controlled G2 progression, upregulated cyclin-dependent kinase 1(CDK1)/cyclin B1, and activated the survival cascade Phosphoinositide 3-kinase (PI3K)/AKT. MEP50 promoted cell migration, and activated the cell migration pathways such as Ras-related C3 botulinum toxin substrate 1 (Rac1)/vasodilator-stimulated phosphoprotein (VASP), and forkhead box protein A2 (FOXA2)/slug/cadherin cascades. Further analyses revealed that MEP50 activated the survival factor PI3K through PRMT5-catalyzed dimethylation of PI3K. Collectively, it is concluded that MEP50 can transform cells independent of AR and ER, and PRMT5 has partial contribution to that process.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1873-3913
Volume :
26
Issue :
12
Database :
MEDLINE
Journal :
Cellular signalling
Publication Type :
Academic Journal
Accession number :
25277535
Full Text :
https://doi.org/10.1016/j.cellsig.2014.09.014