Advertisement
JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1074/jbc.R500010200 on August 1, 2005

J. Biol. Chem., Vol. 280, Issue 39, 33097-33100, September 30, 2005
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
280/39/33097    most recent
R500010200v1
Right arrow Submit a Letter to Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Westerheide, S. D.
Right arrow Articles by Morimoto, R. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Westerheide, S. D.
Right arrow Articles by Morimoto, R. I.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Minireview

Heat Shock Response Modulators as Therapeutic Tools for Diseases of Protein Conformation*

Sandy D. Westerheide and Richard I. Morimoto1

From the Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208


   ABSTRACT
TOP
 ABSTRACT
Heat Shock Proteins: Functions...
 Regulation of the Heat...
 Small Molecule Regulators of...
 Prospectus
 REFERENCES
 
The disruption of protein folding quality control results in the accumulation of a non-native protein species that can form oligomers, aggregates, and inclusions indicative of neurodegenerative disease. Likewise for over 100 other human diseases of protein confirmation, a common feature may be the formation of off-pathway folding intermediates that are unstable, self-associate, and with time lead to a chronic imbalance in protein homeostasis with deleterious consequences on cellular function. This has led to a hypothesis that enhancement of components of the cellular quality control machinery, specifically the levels and activities of molecular chaperones, suppress aggregation and toxicity phenotypes to allow cellular function to be restored. This review addresses the regulation of molecular chaperones and components of protein homeostasis by heat shock transcription factor 1 (HSF1), the master stress-inducible regulator, and our current understanding of pharmacologically active small molecule regulators of the heat shock response as a therapeutic strategy for protein conformational diseases.


   Heat Shock Proteins: Functions in Normal and Disease States
TOP
 ABSTRACT
 Heat Shock Proteins: Functions...
Regulation of the Heat...
 Small Molecule Regulators of...
 Prospectus
 REFERENCES
 
The heat shock response (HSR)2 is an ordered genetic response to diverse environmental and physiological stressors that results in the immediate induction of genes encoding molecular chaperones, proteases, and other proteins essential for protection and recovery from cellular damage associated with the expression of misfolded proteins (Fig. 1). The list of "stressors" that activate transcription of these heat shock genes is large and includes various acute and chronic conditions such as elevated temperatures, heavy metals, small molecule chemical toxicants, infection, and oxidative stress. Mutations and environmental influences including inflammation, ischemia, tissue wounding and repair, cancer, and neurodegenerative diseases are also associated with the aberrant expression of heat shock proteins.

The heat shock gene superfamily is organized by molecular size and functional class, including the Hsp100, Hsp90, Hsp70, Hsp60, Hsp40 (J-domain proteins), and small heat shock protein (sHsp) families. Many of these proteins function as molecular chaperones to guide conformational states critical in the synthesis, folding, translocation, assembly, and degradation of proteins (1, 2). As chaperones are also central components in many signal transduction pathways (3), the proper regulation of chaperone expression is critical to the health of the cell.

Cytoprotection—Heat shock proteins function at the cellular level to protect cells against a wide array of acute and chronic stress conditions. Subacute activation of the HSR results in stress tolerance and cytoprotection against otherwise lethal exposures to stress-induced molecular damage. This protective and adaptive response, also known as induced thermotolerance, ensures that the cell responds rapidly to repeated sub-acute challenges by diverse conditions of cell stress (4). The ability of heat shock proteins to protect against cell damage extends to pathophysiology and severe trauma such as ischemic insults to the heart and brain (5, 6). The induction of the HSR, therefore, may have broad therapeutic benefits in the treatment of various types of tissue trauma and disease.

Neurodegenerative Disorders—An increasing number of neurodegenerative disorders are associated with the expression of misfolded proteins and the appearance of non-native structures described as oligomers, protein aggregates, fibrils, or plaques. These include inherited disorders caused by CAG/polyglutamine expansion as occurs in Huntington disease, Kennedy disease, spinocerebellar ataxias, and other related neurodegenerative diseases including Parkinson disease, amyotrophic lateral sclerosis (ALS), and Alzheimer disease (7). The HSR and heat shock proteins have been implicated in many of these neurodegenerative diseases based on the association of chaperones with intracellular aggregates. For example, live cell imaging experiments show that Hsp70 associates transiently with huntingtin aggregates, with association-dissociation properties identical to chaperone interactions with unfolded polypeptides (8). This suggests that these chaperone interactions may reflect the efforts of Hsp70 to direct the unfolding and dissociation of substrates from the aggregate. Moreover, overexpression of the Hsp70 chaperone network suppresses aggregate formation and/or cellular toxicity. Collectively, these observations have led to the hypothesis that the elevated levels of heat shock proteins reduce or dampen aggregate formation and cellular degeneration (9, 10).

Neurodegenerative diseases often occur later in life when heat shock genes seem to be induced poorly (11, 12). The heat shock response has recently been implicated in the regulation of longevity in Caenorhabditis elegans in a pathway that overlaps with the insulin signaling pathway (13, 14). Reduction of heat shock transcription factor HSF1 levels cause a decreased life span in C. elegans, similar to life span effects observed in mutants of Daf-16, a FOXO transcription factor in the insulin signaling pathway. Daf-16 and HSF1 share a subset of downstream target genes, including sHsps. RNA interference experiments show that a decrease in sHsps and other Hsps leads to a decrease in longevity (13, 14). Therefore, in addition to the prevention of diseases of aging, increased levels of heat shock proteins may lead to increases in life span.

Signal Transduction and Cancer—Hsp90 and Hsp70 interact with and regulate many transcription factors, signaling molecules and kinases, including NF-{kappa}B, p53, v-Src, Raf1, Akt, and steroid hormone receptors (3). Tumor cells typically express higher levels of heat shock proteins compared with non-transformed cells, leading to the suggestion that the aberrant expression of chaperones is associated with the tumorigenic state (15). Depletion of Hsp90 function by the inhibitory compound geldanamycin, or of Hsp70 levels by antisense RNAs in transformed cells, leads to cell growth arrest or cell death (16, 17). This has led to an intriguing proposition that tumor cells are dependent on elevated levels of Hsps, perhaps as a generalized mechanism to suppress cumulative mutations that would otherwise result in the expression of deleterious proteins. The chronic up-regulation of heat shock proteins could also promote cancer by the anti-apoptotic functions demonstrated for all chaperones. Hsp70, Hsp40, Hsp27, and Hsp90 act at multiple points in apoptosis, including inhibition of c-Jun NH2 -terminal kinase (JNK) activation, prevention of cytochrome c release, regulation of the apoptosome, prevention of lysosomal membrane permeabilization, and prevention of caspase activation (18). Therefore, compounds that down-regulate the HSR and chaperone levels, when given in combination with chemotherapy, may prove beneficial for cancer treatment.


   Regulation of the Heat Shock Response and HSF1
TOP
 ABSTRACT
 Heat Shock Proteins: Functions...
 Regulation of the Heat...
Small Molecule Regulators of...
 Prospectus
 REFERENCES
 
The heat shock response is regulated at the transcriptional level by the activities of a family of heat shock transcription factors (HSF) (19). Of the three human HSF genes, HSF1,-2, and -4, HSF1 is the best characterized and essential for the heat shock response. The DNA binding and transcriptional activities of HSF1 are stress-inducibly regulated by a multistep activation pathway. HSF1 exists normally in a negatively regulated state as an inert monomer in either the cytoplasmic or nuclear compartments. Upon exposure to a variety of stresses, HSF1 is derepressed, trimerizes, and accumulates in the nucleus. HSF1 trimers bind with high affinity to the heat shock elements (HSEs) consisting of multiple contiguous inverted repeats of the pentamer sequence nGAAn located in the promoter regions of target genes. The HSF1-regulated genes encoding Hsp70, Hsp90, and sHsps are also transcribed constitutively due to multiple basal factors or binding of low levels of HSF1.



View larger version (49K):
[in this window]
[in a new window]
  		FIGURE 1.
The cell stress response. Diverse stressors that activate the heat shock response are indicated. Upon activation, the heat shock transcription factor HSF rapidly induces expression of heat shock proteins, which have roles in preventing protein misfolding, inducing cytoprotection, promoting signaling pathways necessary for cell growth, protecting cells from apoptosis, and inhibiting aging.

 
Although the overwhelming data in the literature support the proximal stress signal for the HSR as the appearance of misfolded proteins and an imbalance of protein homeostasis, other recent observations point to an involvement of additional signaling pathways. Alterations in intracellular redox status caused by changes in temperature or other stresses have been suggested to be involved in the activation of mammalian HSF1 (20). Additionally, recent work has indicated a role for stress-specific pathways in HSF1 activation (21, 22). Studies in Saccharomyces cerevisiae show that two distinct activators of HSF could work through different mechanisms: while HSF-dependent CUP1 expression during glucose starvation requires the Snf1 kinase, HSF-dependent CUP1 activation by heat shock is Snf1-independent (21). A study comparing heat shock and sodium arsenite induction of histone modifications on the murine Hsp70 promoter also shows differential kinase requirements. Sodium arsenite, but not heat shock, induces the phosphorylation of histone H3 in a p38 kinase-dependent manner that is required for Hsp70 transcription (22). Therefore, while many inducers of the HSR may function through a protein unfolding mechanism, these observations suggest that other inducers may work through distinct mechanisms.

HSF1 is post-translationally modified by phosphorylation and sumoylation to achieve further dynamic range (23). Sites of constitutive HSF1 phosphorylation (Ser303, Ser307, and Ser308) appear to be important for the negative regulation of HSF1, whereas sites of inducible phosphorylation (Ser230, Ser326, and Ser419) promote HSF1 activity (24–26). The balance of kinase and phosphatase activities acting on HSF1 is of fundamental importance to regulation of the heat shock response, as suggested by mathematical modeling (27). While HSF1 is sumoylated on lysine 298 in a manner that requires phosphorylation on serines 303 and 307 (28, 29), the role of this modification on HSF1 activity is still unclear.

HSF1 activity in human cells is further regulated by an intranuclear equilibrium between HSEs in the promoters of HSF1-responsive genes and on chromosome 9 where the majority of HSF1 accumulates at a chromosomal site rich in satellite III repetitive sequences (30). These repetitive sequences are comprised of thousands of copies of redundant, degenerate HSEs that are actively transcribed, although the function of these transcripts and their association with the heat shock response is unknown (31).

HSF1 is negatively regulated by feedback control through interaction with Hsp70 and Hsp90 (32). In cells expressing high levels of these chaperones, the inducible expression of heat shock genes is attenuated. Thus, the HSR involves a multistep pathway with both positive and negative regulators, each of which could be small molecule targets.


   Small Molecule Regulators of the Heat Shock Response
TOP
 ABSTRACT
 Heat Shock Proteins: Functions...
 Regulation of the Heat...
 Small Molecule Regulators of...
Prospectus
 REFERENCES
 
Interest in the HSR and chaperones as potential targets for therapeutics has spurred investigations on small molecule regulators of HSF1. Therapeutically active small molecules that regulate HSF1 or modulate chaperone activities could benefit diseases that have in common alterations in protein conformation that cause an imbalance in protein homeostasis. The classes of small molecules that modulate the HSR are represented by a diverse set of chemically unrelated compounds consistent with the various environmental and physiological signaling pathways that induce the HSR (TABLE ONE).


View this table:
[in this window]
[in a new window]
  		TABLE ONE
Compounds that modulate HSF1 activity

 
Activators—Among the initially identified chemical inducers of the HSR are the protein synthesis inhibitor puromycin and amino acid analogue azetidine (33, 34). As this class of compounds results in the expression of prematurely terminated nascent chains or amino acid analogue-containing misfolded proteins, the appearance of misfolded proteins was subsequently proposed as a signal for induction of the HSR. Additional support for protein misfolding as the stress signal came from complementary observations that inhibitors of protein degradation, including the proteasome inhibitors MG132 and lactacystin and the serine protease inhibitors DCIC, TPCK, and TLCK, all induce HSF1 DNA binding, hyperphosphorylation, and the expression of heat shock proteins (35, 36). Presumably HSR activation prevents the accumulation of these degradation-targeted misfolded substrates to minimize their accumulation as oligomers and aggregates.

Another class of activators of the HSR is the fungal antibiotic radicicol and the benzoquinone ansamycin geldanamycin that are inhibitors of Hsp90. Radicicol and geldanamycin were initially identified in screens for anti-cancer drugs and subsequently developed for their potential as cancer therapies (37). 17-AAG, a related analogue of geldanamycin, has completed multi-institution phase I clinical trials and phase II trials are underway (38). Although radicicol and geldanamycin are structurally distinct, both compounds bind to the ATP binding domain of Hsp90 and inhibit the ATPase. Down-regulation of Hsp90 by this class of compounds derepresses HSF1 activity leading to induction of the HSR and the expression of molecular chaperones (39, 40). These results complement observations from genetic studies in S. cerevisiae on the role of Hsp90 as a negative regulator of the HSR (41). Hsp90 inhibitors are likely to have a multitude of cellular effects, including altering protein homeostasis and interfering with autoregulation of HSF1 activity. Radicicol and geldanamycin inhibit the formation of huntingtin aggregates in both a mammalian cell culture model and in a mouse brain slice culture assay, perhaps due to elevated chaperone expression (42, 43).

Many molecules that regulate inflammation can activate the HSR by induction of HSF1, providing a potential link between the HSR and inflammation. The inflammatory response is induced by a signaling cascade involving arachidonic acid release and metabolism. Phospholipase A2, which stimulates arachidonic acid release, and arachidonate itself both activate the HSR (44, 45). The cyclopentenone prostaglandins PGA1, PGA2, and PGJ2, which are produced downstream of arachidonic acid release, also lead to activation of HSF1 (46, 47). This class of prostaglandin contains highly reactive unsaturated carbonyl moieties that readily adduct thiol groups in proteins. Therefore, the mechanism of HSR activation by this class of molecules may also be through alterations in protein homeostasis.

The triterpenoid celastrol and certain structural analogues represent a new class of heat shock inducers that were identified from a consortium screen for compounds that may be beneficial in treating Huntington disease and ALS (48). Celastrol, a natural product derived from the Celastraceae family of plants, potently activates the HSR in mammalian cells (48, 49). Unlike other compounds that activate the HSR with delayed kinetics of induction, celastrol induces HSF1 rapidly with kinetics similar to those observed for heat shock, leading to the complete expression of chaperone genes. The rapid kinetics and an EC50 in the micromolar range may make celastrol or celastrol derivatives a promising candidate for further development as a therapeutic (49).

Co-inducers—Non-steroidal anti-inflammatory drugs (NSAIDS) are an example of a class of compounds that can co-induce the HSR. These compounds partially activate components of the HSR and often work in conjunction with a secondary stress signal for full induction of Hsp70 expression. This class of co-inducers is best represented by the NSAID sodium salicylate that induces HSF1 DNA binding by converting HSF1 from the monomeric to the trimeric state but does not induce HSF1 hyperphosphorylation and heat shock gene transcription (50). Sodium salicylate, however, reduces the temperature required for the HSR into the range attained by febrile conditions. In contrast, other NSAIDs such as indomethacin induce both HSF1 DNA binding and hyperphosphorylation of HSF1 (50, 51). Long term use of NSAIDs for arthritis and other inflammatory diseases is associated with better neurodegenerative disease outcome (52), suggesting a link between the continual up-regulation of the HSR and decreased neurodegenerative disease pathogenesis.

Other compounds suggested to co-induce the HSR are the hydroxylamine derivatives bimoclomol and arimoclomol. Both compounds appear to decrease the temperature threshold for induction of Hsp70, and a potential mechanism is associated with changes in fluidity of the cell membrane (53–55). Bimoclomol acts as a therapeutic for ischemia and wound healing (53), while arimoclomol delays ALS progression in a mouse model (54).

Inhibitors—Only a few compounds have HSR-inhibitory activities. The flavonoid quercetin and the benzylidene lactam compound KNK437 inhibit the HSR, although the targets and mechanisms of action have not been characterized (56, 57). Quercetin dampens multiple aspects of the HSR including reduced HSF1 DNA binding, HSF1 hyperphosphorylation, and Hsp70 expression (56). As inhibition of the levels of chaperones could have a beneficial consequence for cancer therapy, further investigation into HSR inhibitors is warranted.


   Prospectus
TOP
 ABSTRACT
 Heat Shock Proteins: Functions...
 Regulation of the Heat...
 Small Molecule Regulators of...
 Prospectus
REFERENCES
 
The HSR offers great potential as a therapeutic target given the diverse array of human disease pathologies associated with trauma, stress, and the expression of damaged and misfolded proteins. While a number of small molecule regulators of the HSR have already been identified, only celastrol resulted from a high throughput screen. The identification of new small molecule regulators of the HSR together with mechanistic studies on many of the existing compounds will also prove invaluable as tools to dissect further the multistep pathway of the HSR. With the discovery of the molecular targets of these compounds, it should be possible to generate specific activators or inhibitors with increased potency and selectivity. Given the pleiotropic functions of HSF and the Hsps, a major challenge will be developing activators and inhibitors of the HSR that alter the expression of specific chaperones and heat shock-regulated genes with some degree of tissue specificity.


   FOOTNOTES
 
* This minireview will be reprinted in the 2005 Minireview Compendium, which will be available in January, 2006. This work was supported by grants from the National Institute for General Medical Science, National Institutes for Neurological Diseases and Stroke, Rice Institute for Biomedical Research, Huntington Disease Society of America Coalition for the Cure, and Amyotrophic Lateral Sclerosis Association (ALSA) (to R. I. M.), and National Institutes of Health Training Grant in Signal Transduction and Cancer T32 CA70085 (to S. D. W.). Back

1 To whom correspondence should be addressed. Tel.: 847-491-3340; Fax: 847-491-4461; E-mail: r-morimoto{at}northwestern.edu.

2 The abbreviations used are: HSR, heat shock response; HSF1, heat shock transcription factor 1; Hsp, heat shock protein; sHsp, small heat shock protein; ALS, amyotrophic lateral sclerosis; HSE, heat shock element; NSAID, non-steroidal anti-inflammatory drug; DCIC, 3,4-dichloroisocoumarin; TPCK, N-{alpha}-tosyl-L-phenylalanine chloromethyl ketone; TLCK, N-{alpha}-tosyl-L-lysine chloromethyl ketone; MG132, carbobenzoxy-L-leucyl-L-leucyl-leucinal; 17-AAG, 17-N-allylamino-17-demethoxygeldanamycin. Back


   ACKNOWLEDGMENTS
 
We thank Lea Sistonen, Ville Hietakangas, and members of the Morimoto laboratory for helpful comments.



   REFERENCES
TOP
 ABSTRACT
 Heat Shock Proteins: Functions...
 Regulation of the Heat...
 Small Molecule Regulators of...
 Prospectus
 REFERENCES
 

  1. Hartl, F. U. (1996) Nature 381, 571–579[CrossRef][Medline] [Order article via Infotrieve]
  2. Bukau, B., and Horwich, A. L. (1998) Cell 92, 351–366[CrossRef][Medline] [Order article via Infotrieve]
  3. Pratt, W. B., and Toft, D. O. (2003) Exp. Biol. Med. (Maywood) 228, 111–133[Abstract/Free Full Text]
  4. Landry, J., Bernier, D., Chretien, P., Nicole, L. M., Tanguay, R. M., and Marceau, N. (1982) Cancer Res. 42, 2457–2461[Abstract/Free Full Text]
  5. Christians, E. S., Yan, L. J., and Benjamin, I. J. (2002) Crit. Care Med. 30, S43–S50[CrossRef][Medline] [Order article via Infotrieve]
  6. Mestril, R. (2005) Methods 35, 165–169[CrossRef][Medline] [Order article via Infotrieve]
  7. Kakizuka, A. (1998) Trends Genet. 14, 396–402[CrossRef][Medline] [Order article via Infotrieve]
  8. Kim, S., Nollen, E. A., Kitagawa, K., Bindokas, V. P., and Morimoto, R. I. (2002) Nat. Cell Biol. 4, 826–831[CrossRef][Medline] [Order article via Infotrieve]
  9. Warrick, J. M., Chan, H. Y., Gray-Board, G. L., Chai, Y., Paulson, H. L., and Bonini, N. M. (1999) Nat. Genet. 23, 425–428[CrossRef][Medline] [Order article via Infotrieve]
  10. Krobitsch, S., and Lindquist, S. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 1589–1594[Abstract/Free Full Text]
  11. Soti, C., and Csermely, P. (2003) Exp. Gerontol. 38, 1037–1040[CrossRef][Medline] [Order article via Infotrieve]
  12. Shamovsky, I., and Gershon, D. (2004) Mech. Ageing Dev. 125, 767–775[CrossRef][Medline] [Order article via Infotrieve]
  13. Hsu, A. L., Murphy, C. T., and Kenyon, C. (2003) Science 300, 1142–1145[Abstract/Free Full Text]
  14. Morley, J. F., and Morimoto, R. I. (2004) Mol. Biol. Cell 15, 657–664[Abstract/Free Full Text]
  15. Jaattela, M. (1999) Exp. Cell Res. 248, 30–43[CrossRef][Medline] [Order article via Infotrieve]
  16. Nylandsted, J., Rohde, M., Brand, K., Bastholm, L., Elling, F., and Jaattela, M. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 7871–7876[Abstract/Free Full Text]
  17. Whitesell, L., Mimnaugh, E. G., De Costa, B., Myers, C. E., and Neckers, L. M. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 8324–8328[Abstract/Free Full Text]
  18. Mosser, D. D., and Morimoto, R. I. (2004) Oncogene 23, 2907–2918[CrossRef][Medline] [Order article via Infotrieve]
  19. Pirkkala, L., Nykanen, P., and Sistonen, L. (2001) FASEB J. 15, 1118–1131[Abstract/Free Full Text]
  20. Ahn, S. G., and Thiele, D. J. (2003) Genes Dev. 17, 516–528[Abstract/Free Full Text]
  21. Hahn, J. S., and Thiele, D. J. (2004) J. Biol. Chem. 279, 5169–5176[Abstract/Free Full Text]
  22. Thomson, S., Hollis, A., Hazzalin, C. A., and Mahadevan, L. C. (2004) Mol. Cell 15, 585–594[CrossRef][Medline] [Order article via Infotrieve]
  23. Holmberg, C. I., Tran, S. E., Eriksson, J. E., and Sistonen, L. (2002) Trends Biochem. Sci. 27, 619–627[CrossRef][Medline] [Order article via Infotrieve]
  24. Holmberg, C. I., Hietakangas, V., Mikhailov, A., Rantanen, J. O., Kallio, M., Meinander, A., Hellman, J., Morrice, N., MacKintosh, C., Morimoto, R. I., Eriksson, J. E., and Sistonen, L. (2001) EMBO J. 20, 3800–3810[CrossRef][Medline] [Order article via Infotrieve]
  25. Kim, S. A., Yoon, J. H., Lee, S. H., and Ahn, S. G. (2005) J. Biol. Chem. 280, 12653–12657[Abstract/Free Full Text]
  26. Guettouche, T., Boellmann, F., Lane, W. S., and Voellmy, R. (2005) BMC Biochem. 6, 4[Medline] [Order article via Infotrieve]
  27. Rieger, T. R., Morimoto, R. I., and Hatzimanikatis, V. (2005) Biophys. J. 88, 1646–1658[CrossRef][Medline] [Order article via Infotrieve]
  28. Hong, Y., Rogers, R., Matunis, M. J., Mayhew, C. N., Goodson, M. L., Park-Sarge, O. K., and Sarge, K. D. (2001) J. Biol. Chem. 276, 40263–40267[Abstract/Free Full Text]
  29. Hietakangas, V., Ahlskog, J. K., Jakobsson, A. M., Hellesuo, M., Sahlberg, N. M., Holmberg, C. I., Mikhailov, A., Palvimo, J. J., Pirkkala, L., and Sistonen, L. (2003) Mol. Cell. Biol. 23, 2953–2968[Abstract/Free Full Text]
  30. Jolly, C., Morimoto, R., Robert-Nicoud, M., and Vourc'h, C. (1997) J. Cell Sci. 110, 2935–2941[Abstract]
  31. Jolly, C., Metz, A., Govin, J., Vigneron, M., Turner, B. M., Khochbin, S., and Vourc'h, C. (2004) J. Cell Biol. 164, 25–33[Abstract/Free Full Text]
  32. Morimoto, R. I. (1998) Genes Dev. 12, 3788–3796[Free Full Text]
  33. Hightower, L. E. (1980) J. Cell. Physiol. 102, 407–427[CrossRef][Medline] [Order article via Infotrieve]
  34. Lee, Y. J., and Dewey, W. C. (1987) J. Cell. Physiol. 132, 1–11[CrossRef][Medline] [Order article via Infotrieve]
  35. Holmberg, C. I., Illman, S. A., Kallio, M., Mikhailov, A., and Sistonen, L. (2000) Cell Stress Chaperones 5, 219–228[CrossRef][Medline] [Order article via Infotrieve]
  36. Rossi, A., Elia, G., and Santoro, M. G. (1998) J. Biol. Chem. 273, 16446–16452[Abstract/Free Full Text]
  37. Whitesell, L., Bagatell, R., and Falsey, R. (2003) Curr. Cancer Drug Targets 3, 349–358[CrossRef][Medline] [Order article via Infotrieve]
  38. Bagatell, R., and Whitesell, L. (2004) Mol. Cancer Ther. 3, 1021–1030[Abstract/Free Full Text]
  39. Kim, H. R., Kang, H. S., and Kim, H. D. (1999) IUBMB Life 48, 429–433[Medline] [Order article via Infotrieve]
  40. Bagatell, R., Paine-Murrieta, G. D., Taylor, C. W., Pulcini, E. J., Akinaga, S., Benjamin, I. J., and Whitesell, L. (2000) Clin. Cancer Res. 6, 3312–3318[Abstract/Free Full Text]
  41. Duina, A. A., Kalton, H. M., and Gaber, R. F. (1998) J. Biol. Chem. 273, 18974–18978[Abstract/Free Full Text]
  42. Sittler, A., Lurz, R., Lueder, G., Priller, J., Lehrach, H., Hayer-Hartl, M. K., Hartl, F. U., and Wanker, E. E. (2001) Hum. Mol. Genet. 10, 1307–1315[Abstract/Free Full Text]
  43. Hay, D. G., Sathasivam, K., Tobaben, S., Stahl, B., Marber, M., Mestril, R., Mahal, A., Smith, D. L., Woodman, B., and Bates, G. P. (2004) Hum. Mol. Genet. 13, 1389–1405[Abstract/Free Full Text]
  44. Jurivich, D. A., Sistonen, L., Sarge, K. D., and Morimoto, R. I. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 2280–2284[Abstract/Free Full Text]
  45. Jurivich, D. A., Pangas, S., Qiu, L., and Welk, J. F. (1996) J. Immunol. 157, 1669–1677[Abstract]
  46. Ohno, K., Fukushima, M., Fujiwara, M., and Narumiya, S. (1988) J. Biol. Chem. 263, 19764–19770[Abstract/Free Full Text]
  47. Amici, C., Sistonen, L., Santoro, M. G., and Morimoto, R. I. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 6227–6231[Abstract/Free Full Text]
  48. Abbott, A. (2002) Nature 417, 109[Medline] [Order article via Infotrieve]
  49. Westerheide, S. D., Bosman, J. D., Mbadugha, B. N., Kawahara, T. L., Matsumoto, G., Kim, S., Gu, W., Devlin, J. P., Silverman, R. B., and Morimoto, R. I. (2004) J. Biol. Chem. 279, 56053–56060[Abstract/Free Full Text]
  50. Jurivich, D. A., Sistonen, L., Kroes, R. A., and Morimoto, R. I. (1992) Science 255, 1243–1245[Abstract/Free Full Text]
  51. Lee, B. S., Chen, J., Angelidis, C., Jurivich, D. A., and Morimoto, R. I. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 7207–7211[Abstract/Free Full Text]
  52. in t' Veld, B. A., Ruitenberg, A., Hofman, A., Launer, L. J., van Duijn, C. M., Stijnen, T., Breteler, M. M., and Stricker, B. H. (2001) N. Engl. J. Med. 345, 1515–1521[Abstract/Free Full Text]
  53. Vigh, L., Literati, P. N., Horvath, I., Torok, Z., Balogh, G., Glatz, A., Kovacs, E., Boros, I., Ferdinandy, P., Farkas, B., Jaszlits, L., Jednakovits, A., Koranyi, L., and Maresca, B. (1997) Nat. Med. 3, 1150–1154[CrossRef][Medline] [Order article via Infotrieve]
  54. Kieran, D., Kalmar, B., Dick, J. R., Riddoch-Contreras, J., Burnstock, G., and Greensmith, L. (2004) Nat. Med. 10, 402–405[CrossRef][Medline] [Order article via Infotrieve]
  55. Hargitai, J., Lewis, H., Boros, I., Racz, T., Fiser, A., Kurucz, I., Benjamin, I., Vigh, L., Penzes, Z., Csermely, P., and Latchman, D. S. (2003) Biochem. Biophys. Res. Commun. 307, 689–695[CrossRef][Medline] [Order article via Infotrieve]
  56. Nagai, N., Nakai, A., and Nagata, K. (1995) Biochem. Biophys. Res. Commun. 208, 1099–1105[CrossRef][Medline] [Order article via Infotrieve]
  57. Yokota, S., Kitahara, M., and Nagata, K. (2000) Cancer Res. 60, 2942–2948[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 DiabetesHome page
A. A. Gupte, G. L. Bomhoff, R. H. Swerdlow, and P. C. Geiger
Heat Treatment Improves Glucose Tolerance and Prevents Skeletal Muscle Insulin Resistance in Rats Fed a High-Fat Diet
Diabetes, March 1, 2009; 58(3): 567 - 578.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
Y. Tao, J. Hart, L. Lichtenstein, L. J. Joseph, M. J. Ciancio, S. Hu, E. B. Chang, and M. Bissonnette
Inducible heat shock protein 70 prevents multifocal flat dysplastic lesions and invasive tumors in an inflammatory model of colon cancer
Carcinogenesis, January 1, 2009; 30(1): 175 - 182.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
E. Chung and L. A. Leinwand
Rescuing Cardiac Malfunction: The Roles of the Chaperone-Like Small Heat Shock Proteins
Circ. Res., December 5, 2008; 103(12): 1351 - 1353.
[Full Text] [PDF]

Home page
 J Biomol ScreenHome page
Qingyan Au, P. Kanchanastit, J. R. Barber, Shi Chung Ng, and B. Zhang
High-Content Image-Based Screening for Small-Molecule Chaperone Amplifiers in Heat Shock
J Biomol Screen, December 1, 2008; 13(10): 953 - 959.
[Abstract] [PDF]

Home page
 J. Biol. Chem.Home page
M. Fujimoto, K. Oshima, T. Shinkawa, B. B. Wang, S. Inouye, N. Hayashida, R. Takii, and A. Nakai
Analysis of HSF4 Binding Regions Reveals Its Necessity for Gene Regulation during Development and Heat Shock Response in Mouse Lenses
J. Biol. Chem., October 31, 2008; 283(44): 29961 - 29970.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Fujikake, Y. Nagai, H. A. Popiel, Y. Okamoto, M. Yamaguchi, and T. Toda
Heat Shock Transcription Factor 1-activating Compounds Suppress Polyglutamine-induced Neurodegeneration through Induction of Multiple Molecular Chaperones
J. Biol. Chem., September 19, 2008; 283(38): 26188 - 26197.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. D. Steele, G. Hutter, W. S. Jackson, F. L. Heppner, A. W. Borkowski, O. D. King, G. J. Raymond, A. Aguzzi, and S. Lindquist
Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease
PNAS, September 9, 2008; 105(36): 13626 - 13631.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
R. Rao, W. Fiskus, Y. Yang, P. Lee, R. Joshi, P. Fernandez, A. Mandawat, P. Atadja, J. E. Bradner, and K. Bhalla
HDAC6 inhibition enhances 17-AAG-mediated abrogation of hsp90 chaperone function in human leukemia cells
Blood, September 1, 2008; 112(5): 1886 - 1893.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
M. Zajac, M. V. Moneo, A. Carnero, J. Benitez, and B. Martinez-Delgado
Mitotic catastrophe cell death induced by heat shock protein 90 inhibitor in BRCA1-deficient breast cancer cell lines
Mol. Cancer Ther., August 1, 2008; 7(8): 2358 - 2366.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
R. I. Morimoto
Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging
Genes & Dev., June 1, 2008; 22(11): 1427 - 1438.
[Abstract] [Full Text] [PDF]

Home page
 Eukaryot CellHome page
N. Yamamoto, Y. Maeda, A. Ikeda, and H. Sakurai
Regulation of Thermotolerance by Stress-Induced Transcription Factors in Saccharomyces cerevisiae
Eukaryot. Cell, May 1, 2008; 7(5): 783 - 790.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. Roesslein, D. Schibilsky, L. Muller, U. Goebel, C. Schwer, M. Humar, R. Schmidt, K. K. Geiger, H. L. Pahl, B. H. J. Pannen, et al.
Thiopental Protects Human T Lymphocytes from Apoptosis in Vitro via the Expression of Heat Shock Protein 70
J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 217 - 225.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
A. Trott, J. D. West, L. Klaic, S. D. Westerheide, R. B. Silverman, R. I. Morimoto, and K. A. Morano
Activation of Heat Shock and Antioxidant Responses by the Natural Product Celastrol: Transcriptional Signatures of a Thiol-targeted Molecule
Mol. Biol. Cell, March 1, 2008; 19(3): 1104 - 1112.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
W. E. Balch, R. I. Morimoto, A. Dillin, and J. W. Kelly
Adapting Proteostasis for Disease Intervention
Science, February 15, 2008; 319(5865): 916 - 919.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. Chung, A.-K. Nguyen, D. C. Henstridge, A. G. Holmes, M. H. S. Chan, J. L. Mesa, G. I. Lancaster, R. J. Southgate, C. R. Bruce, S. J. Duffy, et al.
HSP72 protects against obesity-induced insulin resistance
PNAS, February 5, 2008; 105(5): 1739 - 1744.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
C. Boyault, Y. Zhang, S. Fritah, C. Caron, B. Gilquin, S. H. Kwon, C. Garrido, T.-P. Yao, C. Vourc'h, P. Matthias, et al.
HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates
Genes & Dev., September 1, 2007; 21(17): 2172 - 2181.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Sakurai and Y. Takemori
Interaction between Heat Shock Transcription Factors (HSFs) and Divergent Binding Sequences: BINDING SPECIFICITIES OF YEAST HSFs AND HUMAN HSF1
J. Biol. Chem., May 4, 2007; 282(18): 13334 - 13341.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. Zourlidou, T. Gidalevitz, M. Kristiansen, C. Landles, B. Woodman, D. J. Wells, D. S. Latchman, J. de Belleroche, S. J. Tabrizi, R. I. Morimoto, et al.
Hsp27 overexpression in the R6/2 mouse model of Huntington's disease: chronic neurodegeneration does not induce Hsp27 activation
Hum. Mol. Genet., May 1, 2007; 16(9): 1078 - 1090.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Hashikawa, N. Yamamoto, and H. Sakurai
Different Mechanisms Are Involved in the Transcriptional Activation by Yeast Heat Shock Transcription Factor through Two Different Types of Heat Shock Elements
J. Biol. Chem., April 6, 2007; 282(14): 10333 - 10340.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. Ostling, J. K. Bjork, P. Roos-Mattjus, V. Mezger, and L. Sistonen
Heat Shock Factor 2 (HSF2) Contributes to Inducible Expression of hsp Genes through Interplay with HSF1
J. Biol. Chem., March 9, 2007; 282(10): 7077 - 7086.
[Abstract] [Full Text] [PDF]

Home page
 Journals of Gerontology Series A: Biological Sciences and Medical SciencesHome page
N. Widodo, C. C. Deocaris, K. Kaur, K. Hasan, T. Yaguchi, K. Yamasaki, T. Sugihara, T. Ishii, R. Wadhwa, and S. C. Kaul
Stress Chaperones, Mortalin, and Pex19p Mediate 5-Aza-2' Deoxycytidine-Induced Senescence of Cancer Cells by DNA Methylation-Independent Pathway
J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2007; 62(3): 246 - 255.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. R. Sekhar, V. N. Sonar, V. Muthusamy, S. Sasi, A. Laszlo, J. Sawani, N. Horikoshi, R. Higashikubo, R. G. Bristow, M. J. Borrelli, et al.
Novel Chemical Enhancers of Heat Shock Increase Thermal Radiosensitization through a Mitotic Catastrophe Pathway
Cancer Res., January 15, 2007; 67(2): 695 - 701.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. G. Evans, S. Wisen, and J. E. Gestwicki
Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid beta-(1-42) Aggregation in Vitro
J. Biol. Chem., November 3, 2006; 281(44): 33182 - 33191.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. D. Westerheide, T. L. A. Kawahara, K. Orton, and R. I. Morimoto
Triptolide, an Inhibitor of the Human Heat Shock Response That Enhances Stress-induced Cell Death
J. Biol. Chem., April 7, 2006; 281(14): 9616 - 9622.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
J. D. Johnson and M. Fleshner
Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72
J. Leukoc. Biol., March 1, 2006; 79(3): 425 - 434.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
280/39/33097    most recent
R500010200v1
Right arrow Submit a Letter to Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Westerheide, S. D.
Right arrow Articles by Morimoto, R. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Westerheide, S. D.
Right arrow Articles by Morimoto, R. I.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
Advertisement
spacer
Advertisement
Advertisement