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TitleAbsence of ataxin-3 leads to cytoskeletal disorganization and increased cell death
Author(s)Rodrigues, Ana João
Costa, Maria do Carmo
Silva, Teresa L
Ferreira, Daniela
Bajanca, Fernanda
Santos, Elsa Clara Carvalho Logarinho
Maciel, P.
Keywords3T3 Cells
Blotting, Western
Cell Cycle
Focal adhesions
HeLa Cells
In situ nick-end labeling
Integrin alpha1
Microscopy, Confocal
Nerve tissue proteins
Nuclear proteins
RNA interference
Repressor proteins
Reverse transcriptase polymerase chain reaction
Transcription factors
Sinocerebellar ataxia type 3
Issue dateOct-2010
JournalBiochimica et Biophysica Acta (BBA). Molecular Cell Research
Abstract(s)Ataxin-3 (ATXN3) is a widely expressed protein that binds to ubiquitylated proteins, has deubiquitylating activity in vitro and is thought to modulate substrate degradation through the ubiquitin-proteasome pathway. Expansion of a polyglutamine tract in ATXN3 causes Machado-Joseph disease, a late-onset neurodegenerative disorder characterized by ubiquitin-positive aggregate formation and specific neuronal death. Although ATXN3 has been involved in transcriptional repression and in the ubiquitin-proteasome pathway, its biological function is still unknown. In this work, we show that depletion of ATXN3 using small-interference RNA (siRNA) causes a prominent phenotype in both human and mouse cell lines. A mild increase in ubiquitylation occurs and cells exhibit ubiquitin-positive foci, which is consistent with ATXN3 putative function as a deubiquitylating enzyme. In addition, siATXN3-silenced cells exhibit marked morphological changes such as rounder shape and loss of adhesion protrusions. At a structural level, the microtubule, microfilament and intermediate filament networks are severely compromised and disorganized. This cytoskeletal phenotype is reversible and dependent on ATXN3 levels. Cell-extracellular matrix connection is also affected in ATXN3-depleted cells as talin expression is reduced in the focal adhesions and lower levels of alpha-1 integrin subunit are expressed at their surface. Although the cytoskeletal and adhesion problems do not originate any major change in the cell cycle of siATXN3-depleted cells, cell death is increased in siATXN3 cultures compared to controls. In summary, in this work we show that the absence of ATXN3 leads to an overt cytoskeletal/adhesion defect raising the possibility that this protein may play a role in the cytoskeleton.
Publisher version
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Appears in Collections:ICVS - Artigos em revistas internacionais / Papers in international journals

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