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1.
Biochim Biophys Acta ; 1838(1 Pt B): 482-92, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24099741

RESUMEN

Neutral lipid transport in mammals is complicated involving many types of apolipoprotein. The exchangeable apolipoproteins mediate the transfer of hydrophobic lipids between tissues and particles, and bind to cell surface receptors. Amphipathic α-helices form a common structural motif that facilitates their lipid binding and exchangeability. ApoLp-III, the only exchangeable apolipoprotein found in insects, is a model amphipathic α-helix bundle protein and its three dimensional structure and function mimics that of the mammalian proteins apoE and apoAI. Even the intracellular exchangeable lipid droplet protein TIP47/perilipin 3 contains an α-helix bundle domain with high structural similarity to that of apoE and apoLp-III. Here, we investigated the interaction of apoLp-III from Locusta migratoria with lipid monolayers. Consistent with earlier work we find that insertion of apoLp-III into fluid lipid monolayers is highest for diacylglycerol. We observe a preference for saturated and more highly ordered lipids, suggesting a new mode of interaction for amphipathic α-helix bundles. X-ray reflectivity shows that apoLp-III unfolds at a hydrophobic interface and flexible loops connecting the amphipathic α-helices stay in solution. X-ray diffraction indicates that apoLp-III insertion into diacylglycerol monolayers induces additional ordering of saturated acyl-chains. These results thus shed important new insight into the protein-lipid interactions of a model exchangeable apolipoprotein with significant implications for its mammalian counterparts.


Asunto(s)
Apolipoproteínas/química , Diglicéridos/química , Proteínas de Insectos/química , Fosfolípidos/química , Liposomas Unilamelares/química , Animales , Interacciones Hidrofóbicas e Hidrofílicas , Locusta migratoria/química , Estructura Secundaria de Proteína , Desplegamiento Proteico , Dispersión del Ángulo Pequeño , Difracción de Rayos X
2.
Pigment Cell Melanoma Res ; 30(5): 477-487, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28544727

RESUMEN

To mitigate melanoma risk, sunscreen use is widely advocated; yet, the ability of sunscreens to prevent melanoma remains controversial. Here, we test the tenet that sunscreens limit melanoma risk by blocking ultraviolet radiation (UV)-induced DNA damage using murine models that recapitulate the genetics and spontaneous evolution of human melanoma. We find that a single, non-erythematous dose of UV dramatically accelerates melanoma onset and increases tumor multiplicity in mice carrying an endogenous, melanocyte-specific NRas61R allele. By contrast, transient UV exposure does not alter tumor onset in mice lacking p16INK4a or harboring an NRas12D allele. To block the rapid onset of melanoma cooperatively caused by UV and NRas61R , we employed a variety of aerosol sunscreens. While all sunscreens delayed melanoma formation and blocked UV-induced DNA damage, differences in aerosol output (i.e., amount applied/cm2 ) caused variability in the cancer preventative efficacy of products with identical sunburn protection factor (SPF) ratings.


Asunto(s)
Carcinogénesis/patología , Carcinogénesis/efectos de la radiación , Melanoma/tratamiento farmacológico , Melanoma/patología , Mutación/genética , Neoplasias Cutáneas/tratamiento farmacológico , Protectores Solares/uso terapéutico , Rayos Ultravioleta , Proteínas ras/genética , Aerosoles , Animales , Codón/genética , Daño del ADN , Supervivencia sin Enfermedad , Relación Dosis-Respuesta en la Radiación , Ratones Endogámicos C57BL , Neoplasias Cutáneas/patología , Factor de Protección Solar
3.
Cancer Discov ; 4(12): 1418-29, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25252692

RESUMEN

UNLABELLED: NRAS mutation at codons 12, 13, or 61 is associated with transformation; yet, in melanoma, such alterations are nearly exclusive to codon 61. Here, we compared the melanoma susceptibility of an NrasQ61R knock-in allele to similarly designed KrasG12D and NrasG12D alleles. With concomitant p16INK4a inactivation, KrasG12D or NrasQ61R expression efficiently promoted melanoma in vivo, whereas NrasG12D did not. In addition, NrasQ61R mutation potently cooperated with Lkb1/Stk11 loss to induce highly metastatic disease. Functional comparisons of NrasQ61R and NrasG12D revealed little difference in the ability of these proteins to engage PI3K or RAF. Instead, NrasQ61R showed enhanced nucleotide binding, decreased intrinsic GTPase activity, and increased stability when compared with NrasG12D. This work identifies a faithful model of human NRAS-mutant melanoma, and suggests that the increased melanomagenecity of NrasQ61R over NrasG12D is due to heightened abundance of the active, GTP-bound form rather than differences in the engagement of downstream effector pathways. SIGNIFICANCE: This work explains the curious predominance in human melanoma of mutations of codon 61 of NRAS over other oncogenic NRAS mutations. Using conditional "knock-in" mouse models, we show that physiologic expression of NRASQ61R, but not NRASG12D, drives melanoma formation.


Asunto(s)
Transformación Celular Neoplásica/genética , Codón , Genes ras , Melanoma/genética , Mutación , Quinasas de la Proteína-Quinasa Activada por el AMP , Alelos , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Eliminación de Gen , Orden Génico , Sitios Genéticos , Genotipo , Guanosina Trifosfato/metabolismo , Humanos , Melanoma/metabolismo , Melanoma/mortalidad , Melanoma/patología , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Metástasis de la Neoplasia , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Carga Tumoral
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