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PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma
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نویسنده
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pytel d. ,gao y. ,mackiewicz k. ,katlinskaya y.v. ,staschke k.a. ,paredes m.c.g. ,yoshida a. ,qie s. ,zhang g. ,chajewski o.s. ,wu l. ,majsterek i. ,herlyn m. ,fuchs s.y. ,diehl j.a.
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منبع
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plos genetics - 2016 - دوره : 12 - شماره : 12
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چکیده
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The unfolded protein response (upr) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. perk,a upr protein kinase,regulates protein synthesis and while linked with cell survival,exhibits activities associated with both tumor progression and tumor suppression. for example,while cells lacking perk are sensitive to upr-dependent cell death,acute activation of perk triggers both apoptosis and cell cycle arrest,which would be expected to contribute tumor suppressive activity. we have evaluated these activities in the braf-dependent melanoma and provide evidence revealing a complex role for perk in melanoma where a 50% reduction is permissive for brafv600e-dependent transformation,while complete inhibition is tumor suppressive. consistently,perk mutants identified in human melanoma are hypomorphic with dominant inhibitory function and pro-tumorigenic. strikingly,we demonstrate that small molecule perk inhibitors exhibit single agent efficacy against brafv600e-dependent tumors highlighting the clinical value of targeting perk. © 2016 pytel et al.
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آدرس
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department of biochemistry and molecular biology,hollings cancer center,medical university of south carolina,charleston,sc, United States, department of biochemistry and molecular biology,hollings cancer center,medical university of south carolina,charleston,sc, United States, department of biochemistry and molecular biology,hollings cancer center,medical university of south carolina,charleston,sc, United States, department of biomedical sciences,school of veterinary medicine,university of pennsylvania,philadelphia,pa, United States, oncology discovery research,lilly research laboratories,eli lilly and company,lilly corporate center dc1104,indianapolis,in, United States, oncology discovery research,lilly research laboratories,eli lilly and company,lilly corporate center dc1104,indianapolis,in, United States, department of biochemistry and molecular biology,hollings cancer center,medical university of south carolina,charleston,sc, United States, department of biochemistry and molecular biology,hollings cancer center,medical university of south carolina,charleston,sc, United States, molecular and cellular oncogenesis program,the wistar institute,philadelphia,pa, United States, department of pathology and laboratory medicine,medical university of south carolina,charleston,sc, United States, molecular and cellular oncogenesis program,the wistar institute,philadelphia,pa, United States, department of clinical chemistry and biochemistry,medical university of lodz,lodz, Poland, molecular and cellular oncogenesis program,the wistar institute,philadelphia,pa, United States, department of biomedical sciences,school of veterinary medicine,university of pennsylvania,philadelphia,pa, United States, department of biochemistry and molecular biology,hollings cancer center,medical university of south carolina,charleston,sc, United States
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Authors
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