Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Light-induced apoptosis of photoreceptors represents an animal model for retinal degeneration. Major human diseases that affect vision, such as age-related macular degeneration (AMD) and some forms of retinitis pigmentosa (RP), may be promoted by light. The receptor mediating light damage, however, has not yet been conclusively identified; candidate molecules include prostaglandin synthase, cytochrome oxidase, rhodopsin, and opsins of the cones and the retinal pigment epithelium (PE). We exposed to bright light two groups of genetically altered mice that lack the visual pigment rhodopsin (Rpe65-/- and Rho-/-). The gene Rpe65 is specifically expressed in the PE and essential for the re-isomerization of all-trans retinol in the visual cycle and thus for the regeneration of rhodopsin after bleaching. Rho-/- mice do not express the apoprotein opsin in photoreceptors, which, consequently, do not contain rhodopsin. We show that photoreceptors lacking rhodopsin in these mice are completely protected against light-induced apoptosis. The transcription factor AP-1, a central element in the apoptotic response to light, is not activated in the absence of rhodopsin, indicating that rhodopsin is essential for the generation or transduction of the intracellular death signal induced by light.
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PMID:Protection of Rpe65-deficient mice identifies rhodopsin as a mediator of light-induced retinal degeneration. 1080 58

In retinitis pigmentosa, retinal detachment, age-related macular degeneration, and glaucoma, retinal neuronal cells are damaged by a common mechanism, apoptosis. Because apoptosis is an active process that requires de novo expression of a "death message", this process can be controlled by inhibiting the expression of the "death message". We first studied whether a retinal ischemia-reperfusion model can be used as a model for retinal neuronal apoptosis. In the retinal ischemia-reperfusion injuries, typical features of apoptosis, including TUNEL-positive cells, DNA ladder formation, and ultrastructural features of apoptosis were found. Using the model, systematic research to identify the "death message" was done by DNA microarray analysis. About 200 messages were found to be up- or down-regulated during the process of retinal ischemia-reperfusion. These genes were divided into four groups: (1) transcription factor genes, (2) cell cycle-related genes, (3) reactive oxygen scavenger genes and (4) molecular chaperon genes. The possible roles of such genes in neuronal apoptosis following retinal ischemia-reperfusion injury were studied. In the model, reactive oxygen species produced by reperfusion was found to generate lipid peroxides and induced up-regulation of a transcription factor, c-Jun, that further induced aberrant expression of cell cycle-related genes such as cyclin D1 in amacrine cells. However, because no controlled expression of cell cycle-related genes takes place in retinal neurons, amacrine cells died by a G1 arrest mechanism. On the other hand, horizontal cells never expressed cyclin D1 and the cells were found to die by necrosis. The study revealed a possible mechanism of retinal neuronal apoptosis and it also became apparent that different types of neurons use different "death messages". Furthermore, the possibility that inhibition of a "death message" sometimes induces necrosis rather than apoptosis was shown. This means that we need to try inhibition of the death mechanism upstream rather than downstream. Administration of thioredoxin, an endogenous reactive oxygen species that blocks generation of lipid peroxides and thus inhibits the death process upstream, was found to be neuroprotective against retinal ischemia-reperfusion injury. Aberrant expression of c-Jun and cyclin D1 was down-regulated by the treatment. Possible roles of caspases were also studied by using the ischemia-reperfusion injury, RCS rat, and excessive light exposure damage in wild type and caspase-1 deficient mice. Also, application of adeno-associated virus that carries Bcl-xL was tested to find possible neuroprotective effects on RCS rats. Our studies showed that caspase-1 played a more important role in the retinal photoreceptors and caspase-3 was important in neurons in the inner nuclear layer. Caspase-2 was found to be a major caspase in the retinal ganglion cell layer. In agreement with the findings, caspase-1 deficient mice showed less prominent light damage than wild type mice. Gene therapy by Bcl-xL was effective to protect retinal photoreceptor damage in RCS rats.
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PMID:[Retinal neuronal cell death: molecular mechanism and neuroprotection]. 1180 59

To understand the mechanisms underlying autosomal dominant progressive retinitis pigmentosa (RP) caused by the mutations of the RP1 gene and to identify molecules that play roles in the early disease process, we used Affymetrix U74Av2 microarrays to compare the gene expression profiles of retinas from Rp1-/- and Rp1+/+ mice at postnatal days (P) 7, 10, 14, 18 and 21. These profiles were independently verified by comparison with results of retinal serial analysis of gene expression, U74Av2 array studies of mouse retinas, real-time PCR and in situ hybridization. We found that the disruption of Rp1 significantly affected the expression of multiple clusters of genes whose products were involved in diverse biological pathways. The molecular responses to the disruption of Rp1 changed dramatically during development and were distinct from responses to the disruption of photoreceptor transcription factors (Crx-/- or Nrl-/-) and a phototransduction molecule (Pde6brd1). We found specific alterations of gene expression in the c-Jun N-terminal kinase (JNK) signaling cascades. Western analysis confirmed that the phosphorylation of key members in the JNK signaling cascades (i.e. JNK1, JNK2, MAP2, MKK4 and c-Jun) is reduced, whereas phospho-ERK and phospho-p38 are unchanged, in Rp1-/- retinas at P18-21. Immunostaining demonstrated that, like Rp1, phospho-JNKs and phospho-MAP2 are present in outer segments of photoreceptors. Our studies reveal unique molecular phenotypes in multiple biological pathways and the specific reduction of JNK signaling cascades in RP1 diseases, and suggest that RP1, a doublecortin-containing microtubule associated protein, and JNK signaling cascades play integral roles in photoreceptor development and maintenance. Our studies further suggest JNK-related therapeutic strategies for RP1 diseases.
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PMID:Distinct gene expression profiles and reduced JNK signaling in retinitis pigmentosa caused by RP1 mutations. 1612 34