The role of p19 and p21 H-Ras proteins and mutants in miRNA expression in cancer and a Costello syndrome cell model

BMC Medical Genetics

Research Article

Roseli García-Cruz¹  Maria Camats¹  Montse Bach-Elias¹  Cristian Taccioli²  Carlo M. Croce²  Chang-Gong Liu²  Stefano Volinia²  George A. Calin³ 

[1] Instituto de Investigaciones Biomédicas de Barcelona- CSIC, C/ Egipcíacas15, 08001, Barcelona, Spain;Ohio State University, Department of Molecular Immunology, Virology and Molecular Genetics, 43210, Columbus, Ohio, USA;Ohio State University, Department of Molecular Immunology, Virology and Molecular Genetics, 43210, Columbus, Ohio, USA;Present address: Departments of Experimental Therapeutics & Cancer Genetics, University of Texas, MD Anderson Cancer Center, 77030, Houston, TX, USA;

关键词: Alternative splicing;    IDX;    H-ras;    p19;    p21;    miRNAs;    Costello syndrome;    H-ras mutants;   

DOI  :  10.1186/s12881-015-0184-z

 received in 2015-01-21, accepted in 2015-06-01,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundP19 H-Ras, a second product derived from the H-Ras gene by alternative splicing, induces a G1/S phase delay, thereby maintaining cells in a reversible quiescence state. When P21 H-Ras is mutated in tumour cells, the alternative protein P19 H-Ras is also mutated. The H-Ras mutation Q61L is frequently detected in different tumours, which acts as constitutive activator of Ras functions and is considered to be a strong activating mutant. Additionally, a rare congenital disorder named Costello Syndrome, is described as a H-Ras disorder in children, mainly due to mutation G12S in p19 and p21 H-Ras proteins, which is present in 90 % of the Costello Syndrome patients. Our aim is to better understand the role of p19 and p21 H-Ras proteins in the cancer and Costello Syndrome development, concerning the miRNAs expression.MethodsTotal miRNAs expression regulated by H-Ras proteins were first analyzed in human miRNA microarrays assays. Previously selected miRNAs, were further analyzed in developed cell lines containing H-Ras protein mutants, that included the G12S Costello Syndrome mutant, with PCR Real-Time Taq Man miRNA Assays primers.ResultsThis study describes how p19 affects the RNA world and shows that: i) miR-342, miR-206, miR-330, miR-138 and miR-99b are upregulated by p19 but not by p19W164A mutant; ii) anti-miR-206 can restore the G2 phase in the presence of p19; iii) p19 and p21Q61L regulate their own alternative splicing; iv) miR-206 and miR-138 are differentially regulated by p19 and p21 H-Ras and v) P19G12S Costello mutants show a clear upregulation of miR-374, miR-126, miR-342, miR-330, miR-335 and let-7.ConclusionsThese results allow us to conclude that the H-Ras G12S mutation plays an important role in miRNA expression and open up a new line of study to understand the consequences of this mutation on Costello syndrome. Furthermore, they suggest that oncogenes may have a sufficiently important impact on miRNA expression to promote the development of numerous cancers.

【 授权许可】

Unknown   
© García-Cruz et al. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.