RT Journal Article
SR Electronic
T1 DAPK–HSF1 interaction as a positive-feedback mechanism stimulating TNF-induced apoptosis in colorectal cancer cells
JF Journal of Cell Science
JO J. Cell Sci.
FD The Company of Biologists Ltd
SP 5273
OP 5287
DO 10.1242/jcs.157024
VO 127
IS 24
A1 Benderska, Natalya
A1 Ivanovska, Jelena
A1 Rau, Tilman T.
A1 Schulze-Luehrmann, Jan
A1 Mohan, Suma
A1 Chakilam, Saritha
A1 Gandesiri, Muktheshwar
A1 Ziesché, Elisabeth
A1 Fischer, Thomas
A1 Söder, Stephan
A1 Agaimy, Abbas
A1 Distel, Luitpold
A1 Sticht, Heinrich
A1 Mahadevan, Vijayalakshmi
A1 Schneider-Stock, Regine
YR 2014
UL http://jcs.biologists.org/content/127/24/5273.abstract
AB Death-associated protein kinase (DAPK) is a serine-threonine kinase with tumor suppressor function. Previously, we demonstrated that tumor necrosis factor (TNF) induced DAPK-mediated apoptosis in colorectal cancer. However, the protein–protein interaction network associated with TNF–DAPK signaling still remains unclear. We identified HSF1 as a new DAPK phosphorylation target in response to low concentrations of TNF and verified a physical interaction between DAPK and HSF1 both in vitro and in vivo. We show that HSF1 binds to the DAPK promoter. Transient overexpression of HSF1 protein led to an increase in DAPK mRNA level and consequently to an increase in the amount of apoptosis. By contrast, treatment with a DAPK-specific inhibitor as well as DAPK knockdown abolished the phosphorylation of HSF1 at Ser230 (pHSF1Ser230). Furthermore, translational studies demonstrated a positive correlation between DAPK and pHSF1Ser230 protein expression in human colorectal carcinoma tissues. Taken together, our data define a novel link between DAPK and HSF1 and highlight a positive-feedback loop in DAPK regulation under mild inflammatory stress conditions in colorectal tumors. For the first time, we show that under TNF the pro-survival HSF1 protein can be redirected to a pro-apoptotic program.