Control of Cellular Bcl-xL Levels by Deamidation-Regulated Degradation

被引:28
作者
Dho, So Hee [1 ,2 ,3 ]
Deverman, Benjamin E. [1 ,2 ]
Lapid, Carlo [4 ]
Manson, Scott R. [1 ,2 ]
Gan, Lu [1 ,2 ]
Riehm, Jacob J. [1 ,2 ]
Aurora, Rajeev [5 ]
Kwon, Ki-Sun [3 ]
Weintraub, Steven J. [1 ,2 ,6 ,7 ]
机构
[1] Washington Univ, Sch Med, Div Urol, St Louis, MO 63130 USA
[2] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA
[3] Korea Res Inst Biosci & Biotechnol, Aging Res Ctr, Lab Cell Signaling, Taejon, South Korea
[4] Washington Univ, Dept Biol, St Louis, MO 63130 USA
[5] St Louis Univ, Sch Med, Dept Mol Microbiol & Immunol, St Louis, MO USA
[6] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA
[7] St Louis VA Med Ctr, John Cochran Div, Dept Internal Med, St Louis, MO USA
基金
新加坡国家研究基金会;
关键词
BCL-X-L; IN-VITRO; ANTISENSE OLIGONUCLEOTIDE; PROGNOSTIC-SIGNIFICANCE; ISOASPARTATE FORMATION; INTRACELLULAR PH; PEST SEQUENCE; L PROTEIN; EXPRESSION; APOPTOSIS;
D O I
10.1371/journal.pbio.1001588
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The cellular concentration of Bcl-x(L) is among the most important determinants of treatment response and overall prognosis in a broad range of tumors as well as an important determinant of the cellular response to several forms of tissue injury. We and others have previously shown that human Bcl-x(L) undergoes deamidation at two asparaginyl residues and that DNA-damaging antineoplastic agents as well as other stimuli can increase the rate of deamidation. Deamidation results in the replacement of asparginyl residues with aspartyl or isoaspartyl residues. Thus deamidation, like phosphorylation, introduces a negative charge into proteins. Here we show that the level of human Bcl-x(L) is constantly modulated by deamidation because deamidation, like phosphorylation in other proteins, activates a conditional PEST sequence to target Bcl-x(L) for degradation. Additionally, we show that degradation of deamidated Bcl-x(L) is mediated at least in part by calpain. Notably, we present sequence and biochemical data that suggest that deamidation has been conserved from the simplest extant metazoans through the human form of Bcl-x(L), underscoring its importance in Bcl-xL regulation. Our findings strongly suggest that deamidation-regulated Bcl-x(L) degradation is an important component of the cellular rheostat that determines susceptibility to DNA-damaging agents and other death stimuli.
引用
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页数:16
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