title: The role of p19 and p21 H-Ras proteins and mutants in miRNA expression in cancer and a Costello syndrome cell model.
abstract: BACKGROUND
  P19 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.
  
  
  METHODS
  Total 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.
  
  
  RESULTS
  This 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Instituto de Investigaciones Biomédicas de Barcelona- CSIC, C/ Egipcíacas15, 08001, Barcelona, Spain. roseli_760901@hotmail.com.
authors.forename: Roseli
authors.initials: R
authors.lastname: García-Cruz
authors.affiliation: Instituto de Investigaciones Biomédicas de Barcelona- CSIC, C/ Egipcíacas15, 08001, Barcelona, Spain. marie19es@gmail.com.
authors.forename: Maria
authors.initials: M
authors.lastname: Camats
authors.affiliation: Ohio State University, Department of Molecular Immunology, Virology and Molecular Genetics, Columbus, Ohio, 43210, USA. george.calin@osumc.edu.|Present address: Departments of Experimental Therapeutics & Cancer Genetics, University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA. george.calin@osumc.edu.
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: Ohio State University, Department of Molecular Immunology, Virology and Molecular Genetics, Columbus, Ohio, 43210, USA. chang-gong.liu@osumc.edu.
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.affiliation: Ohio State University, Department of Molecular Immunology, Virology and Molecular Genetics, Columbus, Ohio, 43210, USA. s.volinia@gmail.com.
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.affiliation: Ohio State University, Department of Molecular Immunology, Virology and Molecular Genetics, Columbus, Ohio, 43210, USA. Cristian.Taccioli@osumc.edu.
authors.forename: Cristian
authors.initials: C
authors.lastname: Taccioli
authors.affiliation: Ohio State University, Department of Molecular Immunology, Virology and Molecular Genetics, Columbus, Ohio, 43210, USA. croce.5@osumc.edu.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Instituto de Investigaciones Biomédicas de Barcelona- CSIC, C/ Egipcíacas15, 08001, Barcelona, Spain. montse.bach@iibb.csic.es.
authors.forename: Montse
authors.initials: M
authors.lastname: Bach-Elias
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D056685:Costello Syndrome / Q000235:genetics* / Q000473:pathology*; D004622:Embryo, Mammalian; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D035683:MicroRNAs; D050505:Mutant Proteins; D020033:Protein Isoforms; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins