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: 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)

Chemical References

• MicroRNAs
• Mutant Proteins
• Protein Isoforms
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

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)