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Intermediate filament transcription in astrocytes is repressed by proteasome inhibition
Author(s) -
Middeldorp Jinte,
Kamphuis Willem,
Sluijs Jacqueline A.,
Achoui Dalila,
Leenaars Cathalijn H. C.,
Feenstra Matthijs G. P.,
Tijn Paula,
Fischer David F.,
Berkers Celia,
Ovaa Huib,
Quinlan Roy A.,
Hol Elly M.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-127696
Subject(s) - astrogliosis , proteasome , glial fibrillary acidic protein , lactacystin , neurodegeneration , biology , proteasome inhibitor , microbiology and biotechnology , astrocyte , transcription factor , protein degradation , intermediate filament , chemistry , biochemistry , cell , medicine , cytoskeleton , endocrinology , immunology , central nervous system , gene , immunohistochemistry , disease
Increased expression of the astrocytic intermediate filament protein glial fibrillary acidic protein (GFAP) is a characteristic of astrogliosis. This process occurs in the brain during aging and neurodegeneration and coincides with impairment of the ubiquitin proteasome system. Inhibition of the proteasome impairs protein degradation;therefore, we hypothesized that the increase in GFAP may be the result of impaired proteasomal activity in astrocytes. We investigated the effect of proteasome inhibitors on GFAP expression and other intermediate filament proteins in human astrocytoma cells and in a rat brain model for astrogliosis. Extensive quantitative RT‐PCR, immunocyto‐ chemistry, and Western blot analysis resulted unexpectedly in a strong decrease of GFAP mRNA to <4% of control levels [Control (DMSO) 100±19.2%;proteasome inhibitor (epoxomicin) 3.5±1.3%, n=8;PK0.001] and a loss of GFAP protein in astrocytes in vitro . We show that the proteasome alters GFAP promoter activity, possibly mediated by transcription factors as demonstrated by a GFAP promoter‐luciferase assay and RT 2 Profiler PCR array for human transcription factors. Most important, we demonstrate that proteasome inhibitors also reduce GFAP and vimentin expression in a rat model for induced astrogliosis in vivo . Therefore, proteasome inhibitors could serve as a potential therapy to modulate astrogliosis associated with CNS injuries and disease.— Middeldorp, J.,Kamphuis, W., Sluijs, J. A., Achoui, D., Leenaars, C. H. C., Feenstra, M. G. P., Van Tijn, P., Fischer, D. F., Berkers, C., Ovaa, H., Quinlan, R. A., Hol, E. M. Intermediate filament transcription in astrocytes is repressed by proteasome inhibition. FASEBJ. 23, 2710–2726 (2009)