title: Transcriptional repression and cell death induced by nuclear aggregates of non-polyglutamine protein.
abstract: Nuclear aggregates of polyglutamine (polyQ)-expanded proteins are associated with a number of neurodegenerative diseases including Huntington's disease (HD) and spinocerebellar ataxias (SCAs). The nuclear deposition of polyQ proteins correlates with rearrangements of nuclear matrix, transcriptional dysregulation, and cell death. To explore the requirement for polyQ tracks in educing such cellular responses, we examined whether a non-polyQ protein can deposit as nuclear aggregates and elicit similar responses. We report that a protein chimera (GFP170*) composed of the green fluorescent protein (GFP) fused to an internal fragment of the Golgi Complex Protein (GCP-170) forms nuclear aggregates analogous to those formed by polyQ proteins. Like the polyQ nuclear aggregates, GFP170* inclusions recruit molecular chaperones and proteasomal components, alter nuclear structures containing the promyelocytic leukemia protein (PML), recruit transcriptional factors such as CREB-binding protein (CBP) and p53, repress p53 transcriptional activity, and induce cell death. Our results indicate that nuclear aggregation and transcriptional effects are not unique to polyQ-containing proteins and may represent a general response to misfolded proteins in the nucleus.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, MCLM Room 668, 1530 3rd Avenue South, Birmingham, AL 35294, USA.
authors.forename: Lianwu
authors.initials: L
authors.lastname: Fu
authors.forename: Ya-sheng
authors.initials: YS
authors.lastname: Gao
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sztul
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002522:Chlorocebus aethiops; D000077614:Golgi Matrix Proteins; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D045586:Intranuclear Inclusion Bodies / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D037941:Silencer Elements, Transcriptional / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001324:Autoantigens; C108388:GOLGA3 protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D050506:Mutant Chimeric Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C485192:green fluorescent protein, Aequorea victoria; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D050882:CREB-Binding Protein; C494363:CREBBP protein, human