DAPk1 inhibits NF-魏B activation through TNF-伪 and INF-纬-induced apoptosis

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• 作者：Heon Jong Yoo^a ; ¹ ; Hyun-Jung Byun^b ; ¹ ; Boh-Ram Kim^b ; Ki Hwan Lee^a ; Sang-Yoon Park^b ; Seung Bae Rho^b ; ^{sbrho@ncc.re.kr}
• 关键词：DAPk1 ; death-associated protein kinase 1 ; TNF-伪 ; Tumor necrosis factor alpha ; IFN-纬 ; Interferon-gamma ; siRNA ; short interfering RNA ; PARP ; poly (ADP-ribose) polymerase ; FADD ; Fas-associated protein with death domain ; TRADD ; TNFR-associated death domain
• 刊名：Cellular Signalling
• 出版年：2012
• 期刊代码：42_08986568
• 类别：bio
• 出版时间：July, 2012
• 卷：24
• 期：7
• 页码：1471-1477
• 文件大小：718 K

摘要

Recent studies have shown DAPk as a molecular modulator induced by the second messenger, responsible for controlling cell destiny decisions, but the detailed mechanism mediating the role of DAPk1 during cell death is still not fully understood. In this present report, we attempted to characterize the effects of TNF-伪 and INF-纬 on DAPk1 in human ovarian carcinoma cell lines, OVCAR-3. Both TNF-伪 and INF-纬 significantly induce DAPk1 levels in a time-dependent manner. At the same time, they both arrested cell cycle progression in the G₀-G₁ and G2/M phase, down-regulated cyclin D1, CDK4 and NF-魏B expression, while also up-regulating p27 and p16 expression. Subsequently, the efficacy of the combined treatment with DAPk1 was investigated. In the presence of DAPk1, TNF-伪 or INF-纬-induced apoptosis was additively increased, while TNF-伪 or INF-纬-induced NF-魏B activity was inhibited. Conversely, TNF-伪 or INF-纬-dependent NF-魏B activity was further enhanced by the inhibition of DAPk1 with its specific siRNA. The activity of NF-魏B was dependent on the level of DAPk1, indicating the requirement of DAPk1 for the activation of NF-魏B. Low levels of DAPk1 expression were frequently observed in different human patient's tissue and cancer cell lines compared to normal samples. In addition, over-expression of DAPk1 from either TNF-伪 or INF-纬-treatment cells suppressed the anti-apoptosis protein XIAP as well as COX-2 and ICAM-1, more than control. Taken together, our data findings suggest that DAPk1 can mediate the pro-apoptotic activity of TNF-伪 and INF-纬 via the NF-魏B signaling pathways.