ID: 63. Issue 1 (November 2015)

• Record Type: Journal Article
• Authors: Kalvakolanu, Dhan V.; Gade, Padmaja; Kimball, Amy; Dinardo, Angela C.
• Is Part Of: Cytokine. Volume 76:Issue 1(2015)
• Page Start: 76
• Publication Date: 2015-11
• Subjects: Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2015.08.093
• Languages: English
• ISSNs: 1043-4666

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p id="sp005">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-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7qpc" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e56" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">β</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> regulates the IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7rcx" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e61" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>-induced expression of DAPK1. IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7rcx" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e66" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7qpc" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e71" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">β</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> are obligatory for the formation of ATF6/C/EBP-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7qpc" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e76" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">β</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> transcriptional complex that regulates DAPK1. Our studies show that in B-CLL, failure of IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7rcx" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e82" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> activated functional collaboration between C/EBP-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7qpc" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e87" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">β</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> 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-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7qpc" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e92" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">β</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> activation primary CLL tumors. Restoration of ATF6 or C/EBP-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7qpc" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e97" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">β</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> into respective defective-primary tumor cells, re-established DAPK1 expression. Furthermore, IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7rcx" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e102" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> and chemotherapeutics failed to activate autophagy in CLL patient samples lacking ATF6 or C/EBP-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7qpc" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e107" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">β</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>.Together, these results identify a mechanistic basis for the loss of DAPK1 expression, drug resistance and progression of CLL.</p> </sec> </abstract>