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Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis.
- 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.)
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Animals
Cell Line, Tumor
Cell Movement genetics
Cell Proliferation
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic pathology
Estrogen Receptor alpha metabolism
G2 Phase
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms genetics
Lung Neoplasms pathology
Methylation
Mice, Inbred BALB C
Mice, Nude
Neoplasm Proteins metabolism
Phosphatidylinositol 3-Kinases metabolism
Protein-Arginine N-Methyltransferases metabolism
Proto-Oncogene Proteins c-akt metabolism
Receptors, Androgen metabolism
Signal Transduction
Up-Regulation
Adaptor Proteins, Signal Transducing metabolism
Androgens metabolism
Carcinogenesis metabolism
Estrogens metabolism
Subjects
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