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- Flex, Elisabetta, et al.
(författare)
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Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:16, s. 4315-4327
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Tidskriftsartikel (refereegranskat)abstract
- RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.
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| 2. |
- Lettieri, Raffaella, et al.
(författare)
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DPPTE Thiolipid Self-Assembled Monolayer: A Critical Assay
- 2016
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Ingår i: Langmuir. - : AMER CHEMICAL SOC. - 0743-7463 .- 1520-5827. ; 32:44, s. 11560-11572
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Tidskriftsartikel (refereegranskat)abstract
- Supported lipid membranes represent an elegant way to design a fluid interface able to mimic the physicochemical properties of biological membranes, with potential biotechnological applications. In this work, a diacyl phospholipid, the 1,2-dipalmitoyl-sn-glycero-3-phosphothioethanol (DPPTE), functionalized with a thiol group, was immobilized on a gold surface. In this molecule, the thiol group, responsible for the Au S bond (45 kJ/mol) is located on the phospholipid polar head, letting the hydrophobic chain protrude from the film. This system is widely used in the literature but is no less challenging, since its characterization is not complete, as several discordant data have been obtained. In this work, the film was characterized by cyclic voltammetry blocking experiments, to verify the SAM formation, and by reductive desorption measurements, to estimate the molecular density of DPPTE on the gold surface. This value has been compared to that obtained by quartz crystal microbalance measurements. Ellipsometry and impedance spectroscopy measurements have been performed to obtain information about the monolayer thickness and capacitance. The film morphology was investigated by atomic force microscopy. Finally, Monte Carlo simulations were carried out, in order to gain molecular information about the morphologies of the DPPTE SAM and compare them to the experimental results. We demonstrate that DPPTE molecules, incubated 18 h below the phase transition temperature (T = 41.1 +/- 0.4 degrees C) in ethanol solution, are able to form a self-assembled monolayer on the gold surface, with domain structures of different order, which have never been reported before. Our results make possible rationalization of the scattered results so far obtained on this system, giving a new insight into the formation of phospholipids SAMs on a gold surface.
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