Aberrant Protein Folding as the Molecular Basis of Cancer

Scott, Melissa; Frydman, Judith

doi:10.1385/1-59259-394-1:67

Cited by 27 publications

(24 citation statements)

References 49 publications

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“…For example, mutations in proteins such as p53 and VHL tumor suppressor cause enhanced degradation and subsequent decrease in the concentration of the active functional molecules may lead to tumor development (Scott and Frydman, 2003). It has also been shown that mutations in CFTR impair its correct folding and transport from the endoplasmic reticulum to the plasma membrane, causing loss of CFTR function and cystic fibrosis (Amaral, 2005).…”

Section: Prion Protein Extracellularmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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Section: Prion Protein Extracellularmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…At the molecular level, Hsp70 is a chaperone assisting protein folding/refolding (Beckmann et al, 1990), translocation (Chirico et al, 1988) and degradation (Chiang et al, 1989;Saliba et al, 2002). At the organic level, Hsp70 is associated with ischaemia, neurodegenerative diseases and cancer (Plumier et al, 1995;Cummings et al, 2001;Adachi et al, 2003;Scott and Frydman, 2003;Mosser and Morimoto, 2004). So far, there has been no report about Hsp70's direct role in drug addiction.…”

Section: Introductionmentioning

confidence: 99%

Chaperone heat shock protein 70 in nucleus accumbens core: a novel biological target of behavioural sensitization to morphine in rats

Wang

Qin

Liu

et al. 2013

Int. J. Neuropsychopharm.

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Drug addiction is a major public health issue, yet the underlying adaptation of neural networks by drugs of abuse is not fully understood. We have previously linked chaperone heat shock protein 70 (Hsp70) to drug-induced adaptations. Focusing on the NAc core and shell, the present study aims to provide further findings for our understanding of the relation between behavioural sensitization to morphine and Hsp70 at transcriptional and functional levels in rats. Firstly, we delineated the characteristics of behavioural sensitization induced by a single morphine exposure (1-10 mg/kg, s.c.). Secondly, Hsp70 protein expression in the NAc core was time- and dose-relatedly induced during the development of behavioural sensitization to a single morphine exposure in rats, and Pearson analysis indicated a positive correlation between behavioural sensitization and Hsp70 expression in NAc core. Thirdly, at the transcriptional level, intra-NAc core injection of the specific heat shock factor-I (HSF-I) inhibitor N-Formyl-3,4-methylenedioxy-benzylidine-γ-butyrolactam (KNK437) suppressed Hsp70 expression and the development of behavioural sensitization, while the HSF-I specific inducer geranylgeranylacetone (GGA) promoted both of them. Interestingly, intra-NAc shell injection of KNK437 or GGA did not affect the development of behavioural sensitization. Finally, both the functional inhibition of Hsp70 ATPase activity by methylene blue (MB), and the antagonism of Hsp70 substrate binding site (SBD) activity by pifithrin-μ (PES) impaired the development of behavioural sensitization when they were microinjected into the NAc core. Taken together, the critical involvement of chaperone Hsp70 in behavioural sensitization to morphine identifies a biological target for long-lasting adaptations with relevance to addiction.

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“…At the cellular level, Hsp70 is involved both in cell viability (Angelidis et al 1991(Angelidis et al , 1996 and cell death (Samali and Cotter 1996). Defects in Hsp70 function is often associated with various diseases and pathophysiological situations, including ischemic injury (Plumier et al 1995), neurodegenerative diseases (Cummings et al 2001;Adachi et al 2003), and cancer (Scott and Frydman 2003;Mosser and Morimoto 2004). Structural analysis demonstrated that Hsp70s are composed of two domains, a highly conserved N-terminal ATPase domain of 44 kDa and a less conserved C-terminal domain of 25 kDa (Flaherty et al 1990).…”

Section: Introductionmentioning

confidence: 99%

Hsp70 translocates to the nuclei and nucleoli, binds to XRCC1 and PARP-1, and protects HeLa cells from single-strand DNA breaks

Kotoglou¹,

Kalaitzakis²,

Vezyraki³

et al. 2009

Cell Stress and Chaperones

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For many years, there has been uncertainty concerning the reason for Hsp70 translocation to the nucleus and nucleolus. Herein, we propose that Hsp70 translocates to the nucleus and nucleoli in order to participate in pathways related to the protection of the nucleoplasmic DNA or ribosomal DNA from single-strand breaks. The absence of Hsp70 in HeLa cells, via Hsp70 gene silencing (knockdown), indicated the essential role of Hsp70 in DNA integrity. Therefore, HeLa Hsp70 depleted cells were very sensitive in heat treatment and their DNA breaks were multiple compared to that of control HeLa cells. The molecular mechanism with which Hsp70 performs its role at the level of nucleus and nucleolus during stress was examined. Hsp70 co-localizes with PARP1 in the nucleus/nucleoli as was observed in confocal studies and binds to the BCRT domain of PARP1 as was revealed with protein-protein interaction assays. It was also found that Hsp70 binds simultaneously to XRCC1 and PARP-1,

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Aberrant Protein Folding as the Molecular Basis of Cancer

Cited by 27 publications

References 49 publications

Firefly luciferase mutants as sensors of proteome stress

Firefly luciferase mutants as sensors of proteome stress

Chaperone heat shock protein 70 in nucleus accumbens core: a novel biological target of behavioural sensitization to morphine in rats

Hsp70 translocates to the nuclei and nucleoli, binds to XRCC1 and PARP-1, and protects HeLa cells from single-strand DNA breaks

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