Title |
Transmembrane signal modulation by hyperthermia
|
Institution |
BETH ISRAEL DEACONESS MEDICAL CENTER, BOSTON, MA
|
Principal Investigator |
CALDERWOOD, STUART
|
NCI Program Director |
Rosemary Wong
|
Cancer Activity |
Radiotherapy
|
Division |
DCTD
|
Funded Amount |
$274,025
|
Project Dates |
05/01/1988 - 04/30/2010
|
Fiscal Year |
2009
|
Project Type |
Grant
|
Research Topics w/ Percent Relevance |
Cancer Types w/ Percent Relevance |
Cancer (100.0%)
Metastasis (50.0%)
|
N/A
|
Research Type |
Localized Therapies - Discovery and Development
|
Abstract |
DESCRIPTION (provided by applicant): 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. |