RETRACTED: Identification of phosphorylated p38 as a novel DAPK-interacting partner during TNFalpha-induced apoptosis in colorectal tumor cells.
Death-associated protein kinase (DAPK) is a serine/threonine kinase that contributes to pro-apoptotic signaling on cytokine exposure. The role of DAPK in macrophage-associated tumor cell death is currently unknown. Recently, we suggested a new function for DAPK in the induction of apoptosis during the interaction between colorectal tumor cells and tumor-associated macrophages. Using a cell-culture model with conditioned supernatants of differentiated/activated macrophages (U937) and human HCT116 colorectal tumor cells, we replicated DAPK-associated tumor cell death; this model likely reflects the in vivo tumor setting. In this study, we show that tumor necrosis factor-alpha exposure under conditions of macrophage activation induced DAPK-dependent apoptosis in the colorectal tumor cell line HCT116. Simultaneously, early phosphorylation of p38 mitogen-activated protein kinase (phospho-p38) was observed. We identified the phospho-p38 mitogen-activated protein kinase as a novel interacting protein of DAPK in tumor necrosis factor-alpha-induced apoptosis. The general relevance of this interaction was verified in two colorectal cell lines without functional p53 (ie, HCT116 p53(-/-) and HT29 mutant) and in human colon cancer and ulcerative colitis tissues. Supernatants of freshly isolated human macrophages were also able to induce DAPK and phospho-p38. Our findings highlight the mechanisms that underlie DAPK regulation in tumor cell death evoked by immune cells.
Bajbouj
Khuloud
K
Experimental Tumor Pathology, Institute of Pathology, University of Erlangen-Nuremberg, Universitätsstr. 22, 91054 Erlangen, Germany.
Poehlmann
Angela
A
Kuester
Doerthe
D
Drewes
Thomas
T
Haase
Kathrin
K
Hartig
Roland
R
Teller
Anne
A
Kliche
Stefanie
S
Walluscheck
Diana
D
Ivanovska
Jelena
J
Chakilam
Saritha
S
Ulitzsch
Annika
A
Bommhardt
Ursula
U
Leverkus
Martin
M
Roessner
Albert
A
Schneider-Stock
Regine
R
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D064550:Death-Associated Protein Kinases; D006801:Humans; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases