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.
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Authors | Roseli García-Cruz, Maria Camats, George A Calin, Chang-Gong Liu, Stefano Volinia, Cristian Taccioli, Carlo M Croce, Montse Bach-Elias |
Journal | BMC medical genetics
(BMC Med Genet)
Vol. 16
Pg. 46
(Jul 03 2015)
ISSN: 1471-2350 [Electronic] England |
PMID | 26138095
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- MicroRNAs
- Mutant Proteins
- Protein Isoforms
- Proto-Oncogene Proteins p21(ras)
- ras Proteins
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Topics |
- Animals
- Cell Transformation, Neoplastic
(genetics)
- Cells, Cultured
- Costello Syndrome
(genetics, pathology)
- Embryo, Mammalian
- Gene Expression Regulation, Neoplastic
- HeLa Cells
- Humans
- Mice
- MicroRNAs
(genetics)
- Models, Biological
- Mutant Proteins
(genetics, metabolism)
- Neoplasms
(genetics, metabolism)
- Protein Isoforms
(genetics, physiology)
- Proto-Oncogene Proteins p21(ras)
(genetics, physiology)
- ras Proteins
(genetics, physiology)
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