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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-OTC-K (03))
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Wong, Rosemary S
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Beth Israel Deaconess Medical Center
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Murshid, Ayesha; Prince, Thomas L; Lang, Ben et al. (2018) Role of Heat Shock Factors in Stress-Induced Transcription. Methods Mol Biol 1709:23-34
Murshid, Ayesha; Theriault, Jimmy; Gong, Jianlin et al. (2018) Molecular Chaperone Receptors. Methods Mol Biol 1709:331-344
Eguchi, Takanori; Calderwood, Stuart K; Takigawa, Masaharu et al. (2017) Intracellular MMP3 Promotes HSP Gene Expression in Collaboration With Chromobox Proteins. J Cell Biochem 118:43-51
Calderwood, Stuart K; Gong, Jianlin (2016) Heat Shock Proteins Promote Cancer: It's a Protection Racket. Trends Biochem Sci 41:311-323
Calderwood, Stuart K; Neckers, Len (2016) Hsp90 in Cancer: Transcriptional Roles in the Nucleus. Adv Cancer Res 129:89-106
Gong, J; Weng, D; Eguchi, T et al. (2015) Targeting the hsp70 gene delays mammary tumor initiation and inhibits tumor cell metastasis. Oncogene 34:5460-71
Bunch, Heeyoun; Lawney, Brian P; Lin, Yu-Fen et al. (2015) Transcriptional elongation requires DNA break-induced signalling. Nat Commun 6:10191
Murshid, Ayesha; Gong, Jianlin; Prince, Thomas et al. (2015) Scavenger receptor SREC-I mediated entry of TLR4 into lipid microdomains and triggered inflammatory cytokine release in RAW 264.7 cells upon LPS activation. PLoS One 10:e0122529
Murshid, Ayesha; Gong, Jianlin; Ahmad, Ridwan et al. (2015) Scavenger receptor SREC-I promotes double stranded RNA-mediated TLR3 activation in human monocytes. Immunobiology 220:823-32
Eguchi, Taka; Prince, Thomas; Wegiel, Barbara et al. (2015) Role and Regulation of Myeloid Zinc Finger Protein 1 in Cancer. J Cell Biochem 116:2146-54

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