Extracellular cell stress proteins as biomarkers of human disease

Pockley, A. Graham; Henderson, Brian E.; Multhoff, Gabriele

doi:10.1042/bst20140205

Cited by 36 publications

(29 citation statements)

References 79 publications

(93 reference statements)

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“…The sHSPs have sequence related to the vertebrate lens-crystallins in the eye. A number of sHSPs (HSP17, 25,27) are found to participate, by interaction with the lipids in Journal of Cancer Therapy the membrane, to restore the integrity of the membrane under thermal fluctuations [191] [192]. A cancer cell also acquires thermotolerance which is undesirable in therapeutic treatment.…”

Section: Supporting the Determination Of Early Markers Of Carcinogenementioning

confidence: 99%

“…The HSP members of this family [23] [24] are mainly monomeric proteins that reside in any adenosine-5'-triphosphate (ATP)-containing eukaryotic intracellular compartment and more are found in cell membranes [25]. Human HSP70 proteins can be classified into seven evolutionary groups, with different Cterminal domains and N-terminal domains, which are likely to define their distinctive functions [23].…”

Section: The Hsp 70 Familymentioning

confidence: 99%

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The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Fung¹,

Kong²

2017

JCT

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Heat shock proteins (HSPs) serve to correct proteins' conformation, send the damaged proteins for degradation (quality control function). Heat shock factors (HSFs) are their transcription factors. The protein complexes mTOR1 and 2 (with the same core mTOR), the phosphoinositide-dependent protein kinase-1 (PDK1), the seine/threonine-specific protein kinase (Akt), HSF1, plus their associated proteins form a network participating in protein synthesis, bio-energy generation, signaling for apoptosis with the help of HSPs. A cancer cell synthesizes proteins at fast rate and needs more HSPs to work on quality control. Shutting down this network would lead to cell death. Thus inhibitors of mTOR (mTORI) and inhibitors of HSPs (HSPI) could drive cancer cell to apoptosis-a "passive approach". On the other hand, HSPs form complexes with polypeptides characteristic of the cancer cells; on excretion from the cell, they becomes antigens for the immunity cells, eventually leading to maturation of the cytotoxic T cells, forming the basic principle of preparing cancer-specific, person-specific vaccine. Recent finding shows that HSP70 can penetrate cancer cell and expel its analog to extracellular region, giving the hope to prepare a non-person-specific vaccine covering a variety of cancers. Activation of anti-cancer immunity is the "active approach". On the other hand, mild hyperthermia, with increase of intracellular HSPs, has been found to activate the immunity response, and demonstrate anti-cancer effects. There are certain "mysteries" behind the mechanisms of the active and passive approaches. We analyze the mechanisms involved and provide explanations to some mysteries. We also suggest future research to improve our understanding of these two approaches, in which HSPs play many roles.

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Section: Supporting the Determination Of Early Markers Of Carcinogenementioning

confidence: 99%

Section: The Hsp 70 Familymentioning

confidence: 99%

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Fung¹,

Kong²

2017

JCT

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“…The function of extracellular hsp is apparently different from their chaperone activity inside cells. They appear to act as signaling molecules directed at activating a systemic response to stress (De Maio 2011, Pockley et al 2014, particularly in cells of the immune system (Asea et al 2000, Gastpar et al 2005, Vega et al 2008. The mechanism for the export of extracellular hsp is not clear because they do not contain a consensus secretory signal necessary for their transport via the ER-Golgi compartment.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the first observations of extracellular hsp were ignored for over 20 years (Tytell et al 1986, Hightower andGuidon 1989). Currently, there is extensive evidence for the presence of extracellular hsp, in particular during various pathogenic conditions (De Maio 2011, Pockley et al 2014. Hsp are likely exported by an alternative mechanism independent of the ER-Golgi pathway, termed "the non-classical secretory pathway" (Nickel and Seedorf 2008).…”

Section: Introductionmentioning

confidence: 99%

Bacterial Hsp70 (DnaK) and mammalian Hsp70 interact differently with lipid membranes

López¹,

Cauvi

Arispe

et al. 2016

Cell Stress and Chaperones

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The cellular response to stress is orchestrated by the expression of a family of proteins termed heat shock proteins (hsp) that are involved in the stabilization of basic cellular processes to preserve cell viability and homeostasis. The bulk of hsp function occurs within the cytosol and subcellular compartments. However, some hsp have also been found outside cells released by an active mechanism independent of cell death. Extracellular hsp act as signaling molecules directed at activating a systemic response to stress. The export of hsp requires the translocation from the cytosol into the extracellular milieu across the plasma membrane. We have proposed that membrane insertion is the initial step in this export process. We investigated the interaction of the major inducible hsp from mammalian (Hsp70) and bacterial (DnaK) species with liposomes. We found that mammalian Hsp70 displayed a high specificity for negatively charged phospholipids, such as phosphatidyl serine, whereas DnaK interacted with all lipids tested regardless of the charge. Both proteins were inserted into the lipid bilayer as demonstrated by resistance to acid or basic washes that was confirmed by partial protection from proteolytic cleavage. Several regions of mammalian Hsp70 were inserted into the membrane with a small portion of the N-terminus end exposed to the outer phase of the liposome. In contrast, the N-terminus end of DnaK was inserted into the membrane, exposing the C-terminus end outside the liposome. Mammalian Hsp70 was found to make high oligomeric complexes upon insertion into the membranes whereas DnaK only formed dimers within the lipid bilayer. These observations suggest that both Hsp70s interact with lipids, but mammalian Hsp70 displays a high degree of specificity and structure as compared with the bacterial form.

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“…These proteins can even act as receptors for inflammatory mediators called 'inflammogens' [10]. Support for this new paradigm comes from a number of studies that are highlighted in this issue [11], and a large number of studies that have, and continue to reveal, the presence of a number of HSPs in the bodily fluids of humans and animals [12]. The first two contributions in this issue provide a critical overview of extracellular HSPs [11] and the biology of protein moonlighting [13].…”

Section: Heat Shock Proteins and Protein Moonlightingmentioning

confidence: 99%

Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective

Edkins

Price

Pockley

et al. 2017

Phil. Trans. R. Soc. B

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Many heat shock proteins (HSPs) are essential to survival as a consequence of their role as molecular chaperones, and play a critical role in maintaining cellular proteostasis by integrating the fundamental processes of protein folding and degradation. HSPs are arguably among the most prominent classes of proteins that have been broadly linked to many human disorders, with changes in their expression profile and/or intracellular/extracellular location now being described as contributing to the pathogenesis of a number of different diseases. Although the concept was initially controversial, it is now widely accepted that HSPs have additional biological functions over and above their role in proteostasis (so-called ‘protein moonlighting’). Most importantly, these new insights are enlightening our understanding of biological processes in health and disease, and revealing novel and exciting therapeutic opportunities. This theme issue draws on therapeutic insights from established research on HSPs in cancer and other non-communicable disorders, with an emphasis on how the intracellular function of HSPs contrasts with their extracellular properties and function, and interrogates their potential diagnostic and therapeutic value to the prevention, management and treatment of chronic diseases. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

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Extracellular cell stress proteins as biomarkers of human disease

Cited by 36 publications

References 79 publications

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Bacterial Hsp70 (DnaK) and mammalian Hsp70 interact differently with lipid membranes

Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective

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