Role of the Major Heat Shock Proteins as Molecular Chaperones

Georgopoulos, Costa; Welch, William J.

doi:10.1146/annurev.cb.09.110193.003125

Cited by 1,039 publications

(643 citation statements)

References 127 publications

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“…Such a role for chaperones is consistent with their known functions, i.e. in binding unfolded proteins and peptides and in mediating their translocation across lipid bilayers [30], as well as in enhancing the formation of multimeric protein complexes [8]. This role is supported further by the recent results of Schirmbeck & Reimann [31], Suto & Srivastava [32] and Arnold et al [33], which indicate that the entry of antigenic peptides into the MHC class I pathway can be mediated directly by a molecular chaperone.…”

Section: Discussionsupporting

confidence: 68%

“…Several molecular chaperones have been shown to facilitate the assembly of MHC class I-peptide complexes in the ER by binding to and protecting the unassembled subunits from aggregation [7]. Similarly, chaperones in the cytosol influence the localization, assembly, and turnover of proteins, and therefore may affect the quality or quantity of peptides available for presentation [8]. A specific role for chaperone function in MHC class I-restricted antigen presentation was suggested by Lukacs et al [9], who observed that expression of mycobacterial Hsp65 in a poorly immunogenic tumour cell line resulted in enhanced tumour-specific immunogenicity in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Restoration of MHC Class I Surface Expression and Endogenous Antigen Presentation by a Molecular Chaperone

Wells

Rai²,

Salvato³

et al. 1997

Scand J Immunol

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Wells AD, Rai SK, Salvato MS, Band H, Malkovsky M. Restoration of MHC Class I Surface Expression and Endogenous Antigen Presentation by a Molecular Chaperone. Scand J Immunol 1997;45:605-612 Presentation of cytosolic peptides in the context of major histocompatibility complex (MHC) class I antigen is crucial for immune recognition of virus-infected and malignant cells. This process, which is often defective in cancer cells, involves a series of cellular events which may be facilitated by heat shock proteins (molecular chaperones). To address the influence of chaperone function on the presentation of cytosolic peptides, we have utilized B16 melanoma cells (H-2 b ). These tumour cells are resistant to lysis by MHC class I-restricted cytotoxic T lymphocytes (CTL), due to a very low level of surface MHC expression. The authors found that stably transfected clones of B16 expressing a heterologous heat shock protein (Hsp65) exhibit significantly increased levels of MHC class I antigens on their surface, and are effectively lysed by alloreactive CTL. These MHC class I molecules can form functional MHC-peptide complexes which are recognized by virus-specific CTL. Moreover, mice immunized with Hsp65-expressing tumour cells, but not with control-transfected tumour cells, display a significantly increased resistance to a subsequent challenge with live, wild-type B16. Together, these results indicate that the suitable expression of a molecular chaperone can overcome a defect in MHC class I expression and antigen presentation, and suggest a novel approach to cancer immunotherapy.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Restoration of MHC Class I Surface Expression and Endogenous Antigen Presentation by a Molecular Chaperone

Wells

Rai²,

Salvato³

et al. 1997

Scand J Immunol

View full text Add to dashboard Cite

show abstract

“…Of these proteins, Hsp70s have been most extensively studied [1,2,[6][7][8][10][11][12][13][14][15][16][17][18][19][20][21][22]. A major inducing factor for Hsp70 upregulation is the occurrence of damaged cellular proteins, and the regulation of Hsp70 gene expression occurs mainly at the transcription level [8,9].…”

Section: Introductionmentioning

confidence: 99%

Cloning and expression of heat shock protein 70 gene in the haemocytes of pearl oyster (Pinctada fucata, Gould 1850) responding to bacterial challenge

Wang

Jian

et al. 2009

Fish & Shellfish Immunology

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“…7 One of the best-characterized biological responses to fever is the induction of heat shock protein (HSP) expression. 8,9 HSPs have the promiscuous ability to chaperone and present a broad repertoire of tumor antigens to dendritic cells, and activate both innate and adaptive antitumor immune responses [10][11][12][13][14] and have been extensively tested in clinical trials. [15][16][17] For example, vaccination with autologous tumor-derived HSP gp96-peptide complexes (HSPPC-96), extracted from autologous resected tumors, has been shown to stimulate tumor antigen-specific immune responses in patients with renal cell carcinoma and melanoma in clinical studies.…”

Section: Introductionmentioning

confidence: 99%

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

Li¹,

Liu

Xr³

et al. 2008

Gene Ther

105

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Our pre-clinical studies demonstrated that intratumoral vaccination with a recombinant oncolytic type 2 adenovirus overexpressing the heat shock protein (HSP)70 protein, designated as H103, can inhibit primary and metastatic tumors through enhanced oncolytic activity and HSPmediated immune responses against shared and mutated tumor antigens. In the pre-clinical studies of local H103 administration, no significant toxicity was observed in the animal trials with mice, cavy or rhesus monkeys. A phase I clinical trial of intratumoral injection of H103 was conducted in the patients with advanced solid tumors. A total of 27 patients were injected intratumorally with H103 in a dose-escalation study from a dose of 2.5 Â 10 7 to 3.0 Â 10 12 viral particles (VPs). The maximum tolerated dose of H103 was not defined. Two patients developed dose-limiting toxicities of grade III fever at the dose of 1.5 Â 10 12 VP and transient grade IV thrombocytopenia at the dose of 3.0 Â 10 12 VP. The common adverse events were mainly mild to moderate (grade I/II) in nature, including fever, mild injection-site reaction, leucopenia, lymphopenia, thrombocytopenia and hypochromia. The objective response (complete response+partial response) to H103-injected tumors was 11.1% (3/27), and the clinical benefit rate (complete response+partial response+minor response+stable disease) was 48.1%. Interestingly, transient and partial regression of distant, uninjected tumors was observed in three patients. The numbers of immune cells (CD4 + and CD8 + T cells, and natural killer cells) were elevated after H103 administration, but without statistical significance. This phase I trial demonstrates that intratumoral administration of H103 can be safely applied to cancer patients and shows promising clinical antitumor activity, warranting a further clinical investigation.

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Role of the Major Heat Shock Proteins as Molecular Chaperones

Cited by 1,039 publications

References 127 publications

Restoration of MHC Class I Surface Expression and Endogenous Antigen Presentation by a Molecular Chaperone

Restoration of MHC Class I Surface Expression and Endogenous Antigen Presentation by a Molecular Chaperone

Cloning and expression of heat shock protein 70 gene in the haemocytes of pearl oyster (Pinctada fucata, Gould 1850) responding to bacterial challenge

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

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