We aim to study cell signaling during hyperthermia. We will, therefore, examine how heat stress regulates heat shock protein (HSP) activation. These studies are significant in cancer as HSP expression leads to hyperthermia resistance (thermotolerance). In addition, they are of relevance within a broader context as HSPs protect cells and tissues against degenerative diseases, and declines in HSP expression correlate with the onset of aging. It is thus desirable to understand the regulation of the heat shock response. Our hypothesis is that hyperthermia and pro-degenerative stresses trigger HSP expression through perturbation of mRNA translation in cells. This alteration in cell physiology then leads to activation of factors that can induce HSPs (heat shock transcription factor 1 (HSF1) and MLL1/trithorax) through binding to RNA and phosphorylation by the protein kinase mTOR.
We aim to trace this novel pathway leading from the initial effects of hyperthermia on translation, transmitted to HSF1 through phosphorylation (by the protein kinases PKA and mTOR), leading to facilitated migration of transcription factors to HSP promoters embedded in chromatin and mediation of gene activation. We have proposed the hypothesis that HSF1 and MLL1/trithorax activated by this signaling network then recruit histone modifying enzymes (histone acetylases and histone methyltransferases) to heat shock genes and activate the program of HSP synthesis that underlies cellular homeostasis during hyperthermia.

Public Health Relevance

Cancer cells can be killed by elevated temperatures that are either a few degrees above normal (hyperthermia) or by extremely high temperatures for brief periods (thermal ablation). In each case, tumor cells can resist treatment if they contain proteins that can protect them from heat (heat shock proteins). In this proposal, we will determine how the heat shock proteins are made in the cell and whether their synthesis can become inhibited.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047407-26
Application #
8677567
Study Section
Special Emphasis Panel (ZRG1-OTC-K (03))
Program Officer
Wong, Rosemary S
Project Start
1988-05-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
26
Fiscal Year
2014
Total Cost
$271,814
Indirect Cost
$115,599
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Chou, S-D; Murshid, A; Eguchi, T et al. (2015) HSF1 regulation of ?-catenin in mammary cancer cells through control of HuR/elavL1 expression. Oncogene 34:2178-88
Bunch, Heeyoun; Zheng, Xiaofeng; Burkholder, Adam et al. (2014) TRIM28 regulates RNA polymerase II promoter-proximal pausing and pause release. Nat Struct Mol Biol 21:876-83
Eguchi, Takanori; Watanabe, Ken; Hara, Emilio Satoshi et al. (2013) OstemiR: a novel panel of microRNA biomarkers in osteoblastic and osteocytic differentiation from mesencymal stem cells. PLoS One 8:e58796
Murshid, Ayesha; Eguchi, Takanori; Calderwood, Stuart K (2013) Stress proteins in aging and life span. Int J Hyperthermia 29:442-7
Calderwood, Stuart K; Gong, Jianlin; Stevenson, Mary Ann et al. (2013) Cellular and molecular chaperone fusion vaccines: targeting resistant cancer cell populations. Int J Hyperthermia 29:376-9
Calderwood, Stuart K (2013) Tumor heterogeneity, clonal evolution, and therapy resistance: an opportunity for multitargeting therapy. Discov Med 15:188-94
Murshid, Ayesha; Gong, Jianlin; Calderwood, Stuart K (2013) Purification, preparation, and use of chaperone-peptide complexes for tumor immunotherapy. Methods Mol Biol 960:209-17
Ciocca, Daniel R; Arrigo, Andre Patrick; Calderwood, Stuart K (2013) Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch Toxicol 87:19-48
Calderwood, Stuart K (2012) Elevated levels of HSF1 indicate a poor prognosis in breast cancer. Future Oncol 8:399-401
Zhang, Yue; Murshid, Ayesha; Prince, Thomas et al. (2011) Protein kinase A regulates molecular chaperone transcription and protein aggregation. PLoS One 6:e28950

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