The nuclear matrix is a thermolabile cellular structure

Lepock, James R.; Frey, H.E.; Heynen, Miriam; Senisterra, Guillermo; Warters, Raymond L.

doi:10.1379/1466-1268(2001)006<0136:tnmiat>2.0.co;2

Cited by 49 publications

(39 citation statements)

References 43 publications

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“…It has been suggested that intranuclear inclusion formation of polyQ-expanded ATXN3 is promoted by the nuclear environment (11), and in fact, heat-induced denaturation of proteins is more rapid in the nuclear compartment compared with the cytoplasm, as demonstrated by biophysical (28) and biochemical (29,30) experiments. On the other hand, evidence has been provided that nuclear inclusions are active proteolytic centers (31).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Aggregation of Polyglutamine-expanded Ataxin-3

Breuer

Haacke

Evert

et al. 2010

Journal of Biological Chemistry

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Expansion of a polymorphic polyglutamine segment is the common denominator of neurodegenerative polyglutamine diseases. The expanded proteins typically accumulate in large intranuclear inclusions and induce neurodegeneration. However, the mechanisms that determine the subcellular site and rate of inclusion formation are largely unknown. We found that the conserved putative nuclear localization sequence Arg-LysArg-Arg, which is retained in a highly aggregation-prone fragment of ataxin-3, did not affect the site and degree of inclusion formation in a cell culture model of spinocerebellar ataxia type 3. Addition of synthetic nuclear export or import signals led to the expected localization of ataxin-3 and determined the subcellular site of aggregate formation. Triggering a cellular stress response by heat shock transcription factor ⌬HSF1 coexpression abrogated aggregation in the cytoplasm but not in the nucleus. These findings indicate that native aggregation-prone fragments derived from expanded ataxin-3 may eventually escape the cytoplasmic quality control, resulting in aggregation in the nuclear compartment.Many human diseases are caused by the continuous expression of misfolded or misfolding-sensitive proteins (for review, see Ref. 1). The related polyglutamine (polyQ) 3 family of neurodegenerative diseases is caused by expansion of a variable polyQ segment above a threshold of typically ϳ40 residues. These expansions render the otherwise unrelated proteins susceptible to adopt non-native conformations that eventually become toxic or form toxic oligomers and aggregates. Large aggregates arise as intracellular inclusion bodies that are composed mainly of the mutant protein but also contain many other proteins, including transcription factors (2), molecular chaperones, and components of the ubiquitin-proteasome system (3). Several cellular pathways, including transcriptional dysregulation, inhibition of protein degradation, impairment of energy metabolism, and activation of cell death programs, have been implicated in the molecular mechanisms of the neurodegenerative processes caused by polyQ-expanded proteins (for review, see Ref. 4). These variations are likely determined by sequences outside the polyQ tract, which are specific for the individual disease proteins (5, 6). Even though toxicity has been experimentally dissociated from detectable inclusion body formation (e.g. Refs. 7 and 8), the hallmark of polyQ diseases is the characteristic formation of intraneuronal inclusions, most often in the nuclear compartment. Hence, it seems reasonable to argue that an imbalance in the production of toxic aggregation intermediates and their clearance constitutes the fundamental commonality of these diseases (9). Notably, the aggregation products accumulate, although cells are equipped with an elaborate network of molecular chaperones and cofactors with sufficient capacity to maintain a balanced protein homeostasis essential to cellular function (9, 10). Increasing evidence suggests that the nuclear compartment is the pr...

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Section: Discussionmentioning

confidence: 99%

Nuclear Aggregation of Polyglutamine-expanded Ataxin-3

Breuer

Haacke

Evert

et al. 2010

Journal of Biological Chemistry

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“…(29) The activation energeries for protein denaturization and heat induced cell death were noted to be within the same range. Further research suggested that nuclear proteins are most sensitive (30)(31)(32) and a high degree of correlation of nuclear protein aggregation and heat induced cell kill has been noted. Radiation sensitization is achieved in large part through nuclear protein aggregation which inhibits the DNA repair process thus converting potentially lethal radiation induced DNA breaks into lethal events.…”

Section: Mechanism Of Cell Death With Hyperthermiamentioning

confidence: 99%

Hyperthermia, Radiation and Chemotherapy: The Role of Heat in Multidisciplinary Cancer Care

Hurwitz

Stauffer

2014

Seminars in Oncology

118

104

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“…Induced Hsp70 protects cells, tissues, and organisms against damage from a wide variety of stressful stimuli (Hightower, 1991;Niu et al, 2006;Wu et al, 1996Wu et al, , 2001. Hsp70 can translocate to the nucleus and accumulate there under heat shock or in other harmful conditions (Chughtai et al, 2001;Lepock et al, 2001;Szekely et al, 1995). However, the potential role of Hsp70 in the regulation of the response to some carcinogenic reagents, such as benzo[a]pyrene (BaP), remains unclear.…”

Section: Introductionmentioning

confidence: 99%