Molecular variation of human HSP90α and HSP90β genes in Caucasians

Passarino, Giuseppe; Cavalleri, Gianpiero L.; Stecconi, Rosalia; Franceschi, Claudio; Altomare, K.; Dato, Serena; Greco, Valentina; Sforza, Luigi Luca Cavalli; Underhill, Peter A.; Benedictis, G. De

doi:10.1002/humu.9141

Cited by 32 publications

(24 citation statements)

References 14 publications

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“…Recently, variations in the Hsp90alpha and Hsp90beta genes in 73 Caucasians have been reported (Passarino et al 2003) and subsequent investigations of their functional effects using a yeast-based assay system revealed that the non-synonymous variant p.Gln488His in the alpha-Hsp90 gene was severely defective (MacLean et al 2005). Altogether 14 variations in the three highly inducible cytosolic Hsp70 genes HSP70-1, HSP70-2 and HSP70-HOM have been described, and some of them have been shown to be associated with various diseases, such as rheumatoid arthritis, multiple sclerosis, insulin-dependent diabetes mellitus and ageing just to name a few (see Singh et al 2004 and references therein).…”

Section: Discussionmentioning

confidence: 99%

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

Bross

Hansen

et al. 2006

J Hum Genet

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Molecular chaperones assist protein folding, and variations in their encoding genes may be disease-causing in themselves or influence the phenotypic expression of disease-associated or susceptibility-conferring variations in many different genes. We have screened three candidate patient groups for variations in the HSPD1 and HSPE1 genes encoding the mitochondrial Hsp60/Hsp10 chaperone complex: two patients with multiple mitochondrial enzyme deficiency, 61 sudden infant death syndrome cases (MIM: #272120), and 60 patients presenting with ethylmalonic aciduria carrying non-synonymous susceptibility variations in the ACADS gene (MIM: *606885 and #201470). Besides previously reported variations we detected six novel variations: two in the bidirectional promoter region, and one synonymous and three non-synonymous variations in the HSPD1 coding region. One of the non-synonymous variations was polymorphic in patient and control samples, and the rare variations were each only found in single patients and absent in 100 control chromosomes. Functional investigation of the effects of the variations in the promoter region and the non-synonymous variations in the coding region indicated that none of them had a significant impact. Taken together, our data argue against the notion that the chaperonin genes play a major role in the investigated diseases. However, the described variations may represent genetic modifiers with subtle effects.

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Section: Discussionmentioning

confidence: 99%

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

Bross

Hansen

et al. 2006

J Hum Genet

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“…23 For this purpose, a sequence of 19 nucleotides derived from the HSP90B target was designed. This oligomer was cloned For personal use only.…”

Section: Abolishing Hsp90␤ Expression Leads To the Initiation Of Apopmentioning

confidence: 99%

“…23 For this purpose, a sequence of 19 nucleotides derived from the HSP90B target was designed. This oligomer was cloned under the H1-RNA promoter, 16 and a new vector was generated for cell transduction.…”

Section: Abolishing Hsp90␤ Expression Leads To the Initiation Of Apopmentioning

confidence: 99%

Antiapoptotic function of Bcl-2 in mast cells is dependent on its association with heat shock protein 90β

Cohen-Saidon

Carmi

Keren

et al. 2006

Blood

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In the present study, we demonstrated that the antiapoptotic function of Bcl-2 in mast cells is significantly dependent on its association with the heat shock protein 90␤ (Hsp90␤). Dissociation of these 2 proteins inhibits the antiapoptotic activity of Bcl-2 by initiating the release of cytochrome c from mitochondria into cytosol and increasing the activity of caspase 3 and caspase 7, resulting in mast-cell apoptosis. The antiapoptotic activity of Bcl-2 was greatly affected by knocking-out specifically Hsp90␤ using the RNA interference approach. Thus, for the first time, it has been shown that Hsp90␤ might modulate the antiapoptotic activity of Bcl-2 at least in mast cells. These find- IntroductionMast cells, the major cellular players in allergy, have been found to exist at a constant number in tissues under normal conditions. This probably reflects an equilibrium between cell migration, proliferation, and apoptosis. 1,2 The biochemical events leading to apoptosis in this cell type have just started to be explored. 2,3 We recently demonstrated the role of Bcl-2 in the prevention of mast-cell apoptosis using a novel antibody originated from phage display library. 4 We constructed an anti-Bcl-2 singlechain Fv connected to 11 amino acids derived from TAT protein, which enabled the antibody to penetrate the cell membrane. The anti-Bcl-2 antibody bound specifically to endogenous Bcl-2, leading to the initiation of the apoptosis cascade. 4 The Bcl2 gene family encodes a series of proteins involved in the regulation of programmed cell death. 5 Members of the family can be grouped into 2 distinct sets with antagonistic functions. Bcl-2, BclX L , Mcl-1, and A1/Bfl-1 have antiapoptotic, protective functions and prevent the activation of downstream death-effector caspase proteases. In contrast, proteins such as Bax, Bak, Bad, and Bid have proapoptotic roles and can antagonize the cell-protective functions of Bcl-2. 5,6 Although it is not fully understood how Bcl-2 family proteins regulate apoptotic pathways, one possible mechanism is that members of this family engage in various protein-protein interactions to form homotypic and heterotypic dimers important for their biologic functions. 7,8 Association of Bcl-2 with other antiapoptotic proteins through Bcl-2 homology (BH) domains prevents changes in mitochondrial membrane potential (⌬⌿ m ) and the release of cytochrome c from mitochondria. 9 The ability of many Bcl-2 family members to form homodimers and heterodimers through their BH domains is important for the activation of specific functions, such as initiating and altering the process of apoptosis and neutralizing these functions in the cells. 10 It was, therefore, postulated that the relative ratio of antiapoptotic to proapoptotic dimers plays a pivotal role in determining the resistance of a cell to apoptosis. However, the function of Bcl-2 has been found to be affected by its association with proteins not belonging to the Bcl-2 family. Recently, it was observed that Bcl-2 is able to act as a "cell-killer" on bindi...

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“…Hsp90 has 2 isoforms, Hsp90a and Hsp90b. Only Hsp90a is exposed to the extracellular space, and the presence of Hsp90a on the cell surface was associated with tumor development and progression, especially with cancer metastasis (8,9). For example, a previous study showed that levels of plasma Hsp90a protein in patients with cancer were significantly associated with cancer progression and metastasis, as well as with age, tumor volume, and estrogen receptor (ER) expression.…”

Section: Introductionmentioning

confidence: 99%

Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses

Shi

Xiaoqing

Lou

et al. 2014

Clinical Cancer Research

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Purpose: Altered expression of heat shock protein 90 alpha (Hsp90a) was associated with tumor development, progression, and metastasis. This study explored plasma levels of Hsp90a protein in patients with lung cancer and other controls to assess its diagnostic value and monitor treatment responses for patients with lung cancer.Experimental Design: A total of 2,247 individuals were recruited and assigned into two cohorts as static and dynamic groups. ELISA analysis and confirmation of plasma Hsp90a protein levels for association with tumor stages and treatment responses, respectively, were performed.Results: The average plasma levels of Hsp90a protein in patients with lung cancer were significantly higher than in healthy controls (P < 0.0001). Plasma levels of Hsp90a protein in patients with advanced lung cancer (stage III-IV) were higher than in patients with early-stage lung cancer (stage I-II; P < 0.001). Using a cutoff value of 56.33 ng/mL to separate lung cancer from other controls, the sensitivity and specificity reached 72.18% (95% CI, 0.695-0.749) and 78.70% (95% CI, 0.761-0.813), respectively. To confirm the different levels in the second cohort, plasma levels of Hsp90a protein showed a statistically significant difference between preoperative and postoperative patients in surgical patient groups (P < 0.007). There was also a statistically significant difference between the disease progressive group and stable disease group, with regard to partial response after chemotherapy (P < 0.0001).Conclusions: This study demonstrated that plasma Hsp90a protein levels are useful as a diagnostic biomarker in lung cancer and predict the responses of patients with lung cancer to chemotherapy. Clin Cancer Res; 20(23); 6016-22. Ó2014 AACR.

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Molecular variation of human HSP90α and HSP90β genes in Caucasians

Cited by 32 publications

References 14 publications

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

Antiapoptotic function of Bcl-2 in mast cells is dependent on its association with heat shock protein 90β

Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses

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