title: Light-induced retinal damage involves tyrosine 33 phosphorylation, mitochondrial and nuclear translocation of WW domain-containing oxidoreductase in vivo.
abstract: WW domain-containing oxidoreductase WOX1, also named WWOX or FOR, is a known proapoptotic protein and a candidate tumor suppressor. Stress stimuli activate WOX1 via tyrosine 33 (Tyr33) phosphorylation and translocation to the mitochondria and nuclei in vitro. Here, the potential role of WOX1 in light-induced retinal degeneration in vivo was investigated. WOX1 is expressed primarily in the inner retina at perinatal stages, whereas an enhanced expression of WOX1, along with its Tyr33 phosphorylation (p-WOX1), is shown specifically in the retinal ganglion cells in adults. Prolonged exposure of mature rats to constant, low-intensity light (500 lux) for 1-2 months resulted in substantial death of photoreceptors and the presence of activated microglia, astrocytes and Muller glial in the outer retina. However, the inner retina was not or barely affected. In the damaged inner and outer nuclear layers of rat retina, WOX1 and p-WOX1 were overly expressed. Also, WOX1 colocalized with fragments of opsin-positive cones. In rd mice with an inherited retinal deficiency, upregulation of WOX1 and p-WOX1 in degenerated retina was observed with age. By electron microscopy, a large number of immunogold particles of WOX1 and p-WOX1 were found in the damaged mitochondria and condensed nuclei of degenerating photoreceptors, indicating that WOX1 undergoes activation and translocation to these organelles. In contrast, little or no WOX1-positive particles were found in the Golgi apparatus. In conclusion, activated WOX1 is likely to exert apoptosis of neuronal cells in the outer retina during the light-induced injury and in mice with an inherited retinal defect.
authors.affiliation: Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan 701, Taiwan, ROC. stchen@mail.ncku.edu
authors.forename: S-T
authors.initials: ST
authors.lastname: Chen
authors.forename: J-I
authors.initials: JI
authors.lastname: Chuang
authors.forename: C-L
authors.initials: CL
authors.lastname: Cheng
authors.forename: L-J
authors.initials: LJ
authors.lastname: Hsu
authors.forename: N-S
authors.initials: NS
authors.lastname: Chang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D002467:Cell Nucleus / Q000201:enzymology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005911:Gliosis / Q000201:enzymology / Q000473:pathology; D008027:Light / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000201:enzymology / Q000528:radiation effects / Q000648:ultrastructure; D009474:Neurons / Q000201:enzymology / Q000528:radiation effects* / Q000648:ultrastructure; D010088:Oxidoreductases / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D010775:Photic Stimulation / Q000009:adverse effects; D010786:Photoreceptor Cells / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects*; D012162:Retinal Degeneration / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D014443:Tyrosine; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C428130:Wwox protein, mouse