ID: 63: Defective IFN-signaling through endoplasmic reticulum causes loss of Autophagy resulting in human chronic lymphocytic leukemia progression

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• 作者：Dhan V. Kalvakolanu ; Padmaja Gade ; Amy Kimball ; Angela C. Dinardo
• 刊名：Cytokine
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：76
• 期：1
• 页码：76
• 全文大小：44 K

文摘

The molecular and genetic bases for the progression of chronic lymphocytic leukemia (CLL), an indolent disease, are poorly understood. The Death associated protein kinase 1 (DAPK1), an IFN-inducible calcium-calmodulin-dependent serine/threonine kinase, is a critical regulator of autophagy and apoptosis. Its expression is frequently suppressed in a wide variety of tumors including CLL. Recently, we have identified a novel non-STAT signaling pathway, where in an endoplasmic resident transcription factor ATF6, in association with the transcription factor C/EBP-尾$\mathrm{尾}$ regulates the IFN-纬$\mathrm{纬}$-induced expression of DAPK1. IFN-纬$\mathrm{纬}$-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-尾$\mathrm{尾}$ are obligatory for the formation of ATF6/C/EBP-尾$\mathrm{尾}$ transcriptional complex that regulates DAPK1. Our studies show that in B-CLL, failure of IFN-纬$\mathrm{纬}$ activated functional collaboration between C/EBP-尾$\mathrm{尾}$ and/or ATF6 contributes to a loss of growth control via autophagy. We also show a correlation between loss of DAPK1 levels and a failure of ATF6 and/or C/EBP-尾$\mathrm{尾}$ activation primary CLL tumors. Restoration of ATF6 or C/EBP-尾$\mathrm{尾}$ into respective defective-primary tumor cells, re-established DAPK1 expression. Furthermore, IFN-纬$\mathrm{纬}$ and chemotherapeutics failed to activate autophagy in CLL patient samples lacking ATF6 or C/EBP-尾$\mathrm{尾}$.Together, these results identify a mechanistic basis for the loss of DAPK1 expression, drug resistance and progression of CLL.