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Title: Overexpression of CERKL, a gene responsible for retinitis pigmentosa in humans, protects cells from apoptosis induced by oxidative stress
Author: Tuson, Miquel
Garanto, Alejandro
Gonzàlez-Duarte, Roser
Marfany i Nadal, Gemma
Keywords: Estrès oxidatiu
Malalties de la retina
Oxidative stress
Retinal diseases
Issue Date: 12-Jan-2009
Publisher: Emory University
Abstract: Purpose: Retinitis pigmentosa (RP), a retinal neurodegenerative disorder characterized by apoptosis of photoreceptorcells, is caused by mutations in many different genes. We analyzed the RP gene ceramide kinase-like (CERKL) to determineCERKL function and contribution to pathogenesis.Methods: RT-PCR was performed to characterize CERKLexpression in many human adult and fetal tissues, includingretina. We analyzed the protein subcellular localization by confocal microscopy and further verified it by sucrose gradients.We performed lipid kinase activity assays. And finally, we studied the effects on cell apoptosis after CERKLoverexpression in transiently transfected cultured cells by propidium iodide staining and poly-(ADP-ribose)-polymerase(PARP) caspase-dependent cleavage.Results: CERKLtranscripts underwent alternative splicing. In the human retina, four different CERKL isoforms of 532,558, 419, and 463 amino acids were expressed. CERKL proteins were mainly localized in the endoplasmic reticulum andGolgi compartments, but they also shifted localization to nuclei and nucleoli. We also found that CERKL prevented cellsfrom entering apoptosis induced by oxidative-stress conditions.Conclusions: CERKL remains a unique orphan lipid kinase in that no candidate substrate has been identified after intenseresearch. The dynamic localization of CERKL suggests multiple sites of action. Remarkably, CERKL (but not the RPR257X mutant) exerts a protective role in cells against oxidative stress, consistent with RP mutations impairing the normalprotein function in photoreceptors and thus tilting the balance toward apoptosis. These results provide valuable insightsinto the molecular mechanisms causing retinal degeneration.
Note: Reproducció del document publicat a:
It is part of: Molecular Vision, 2009, num. 15, p. 168-180
ISSN: 1090-0535
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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