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lüll BimEL as a possible molecular link between proteasome dysfunction and cell death induced by mutant huntingtin Leon R; Bhagavatula N; Ulukpo O; McCollum M; Wei JEur J Neurosci 2010[Jun]; 31 (11): 1915-25Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the N-terminus of the huntingtin protein. It is characterized by a selective loss of medium spiny neurons in the striatum. It has been suggested that impaired proteasome function and endoplasmic reticulum (ER) stress play important roles in mutant huntingtin (mHtt)-induced cell death. However, the molecular link involved is poorly understood. In the present study, we identified the essential role of the extra long form of Bim (Bcl-2 interacting mediator of cell death), BimEL, in mHtt-induced cell death. BimEL protein expression level was significantly increased in cell lines expressing the N-terminus of mHtt and in a mouse model of HD. Although quantitative RT-PCR analysis indicated that BimEL mRNA was increased in cells expressing mHtt, we provided evidence showing that, at the post-translational level, phosphorylation of BimEL played a more important role in regulating BimEL expression. Up-regulation of BimEL facilitated the translocation of Bax to the mitochondrial membrane, which further led to cytochrome c release and cell death. On the other hand, knocking down BimEL expression prevented mHtt-induced cell death. Taken together, these findings suggest that BimEL is a key element in regulating mHtt-induced cell death. A model depicting the role of BimEL in linking mHtt-induced ER stress and proteasome dysfunction to cell death is proposed.|*Nerve Tissue Proteins/genetics/metabolism[MESH]|*Nuclear Proteins/genetics/metabolism[MESH]|Animals[MESH]|Apoptosis Regulatory Proteins/genetics/*metabolism[MESH]|Bcl-2-Like Protein 11[MESH]|Cell Death/*physiology[MESH]|Cell Line[MESH]|Disease Models, Animal[MESH]|Endoplasmic Reticulum/metabolism[MESH]|Enzyme Activation[MESH]|Extracellular Signal-Regulated MAP Kinases/metabolism[MESH]|Humans[MESH]|Huntingtin Protein[MESH]|Huntington Disease/*physiopathology[MESH]|JNK Mitogen-Activated Protein Kinases/metabolism[MESH]|Membrane Proteins/genetics/*metabolism[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Inbred CBA[MESH]|Mice, Transgenic[MESH]|Mitochondria/metabolism[MESH]|Proteasome Endopeptidase Complex/*physiology[MESH]|Proto-Oncogene Proteins/genetics/*metabolism[MESH]|RNA, Small Interfering/genetics/metabolism[MESH]|bcl-2-Associated X Protein/metabolism[MESH] |