PT  - JOURNAL ARTICLE
AU  - Benderska, Natalya
AU  - Ivanovska, Jelena
AU  - Rau, Tilman T.
AU  - Schulze-Luehrmann, Jan
AU  - Mohan, Suma
AU  - Chakilam, Saritha
AU  - Gandesiri, Muktheshwar
AU  - Ziesché, Elisabeth
AU  - Fischer, Thomas
AU  - Söder, Stephan
AU  - Agaimy, Abbas
AU  - Distel, Luitpold
AU  - Sticht, Heinrich
AU  - Mahadevan, Vijayalakshmi
AU  - Schneider-Stock, Regine
TI  - DAPK–HSF1 interaction as a positive-feedback mechanism stimulating TNF-induced apoptosis in colorectal cancer cells
AID  - 10.1242/jcs.157024
DP  - 2014 Dec 15
TA  - Journal of Cell Science
PG  - 5273--5287
VI  - 127
IP  - 24
4099  - http://jcs.biologists.org/content/127/24/5273.short
4100  - http://jcs.biologists.org/content/127/24/5273.full
SO  - J. Cell Sci.2014 Dec 15; 127
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.