The HSP molecular chaperones are primordial proteins involved in cytoprotection during stress in all cellular organism. HSP gene expression is regulated by heat shock transcription factor 1 (HSF1). Maintaining the correct regulation of HSF1 is essential, as elevated HSF1 activity is involved in cancer cell survival and tumor progression while decreased HSF1 activity is involved in neuronal degeneration, aging and sensitivity to stress. We have in the preceding years of this grant characterized a number of regulatory phosphorylation sites HSF1 regulation and determined novel mechanisms for HSF1 regulation. In the current grant proposal we aim to determine: (1) the role of phosphorylation in HSF1 regulation in the cytoplasm. HSF1 is constitutively repressed by a mechanism involving phosphorylation at a key site (serine 121) that regulates HSP90 binding.
We aim to determine how phosphorylation at this site couples the activity of protein kinases to HSF1 regulation though modulating HSF1 interaction with molecular chaperone complexes. (2) Role of HSF1 phosphorylation in association with hsp promoters, transcriptional regulation and histone modification the nucleus. We have found that transcription of HSF1 is regulated by at least 4 phosphorylation sites at serines 195, 303, 307 and threonine 142. In this aim we will determine how phosphorylation regulates HSF1 occupation of hsp promoters and transcriptional activity in vivo and alters interaction with chromatin acetylates, deacetylases and chromatin remodeling proteins.
Our aim will to be to determine how upstream signal transduction networks regulate hsp genes. Understanding the basic pathways of HSF1 regulation will permit us to probe the mechanisms of HSP dysregulation in disease and to modify these pathways. ? ?
| 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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