Alternative splicing and caspase-mediated cleavage generate antagonistic variants of the stress oncoprotein LEDGF/p75

被引:31
作者
Brown-Bryan, Terry A. [1 ,2 ]
Leoh, Lai S. [1 ,2 ]
Ganapathy, Vidya [1 ,2 ]
Pacheco, Fabio J. [1 ,6 ]
Mediavilia-Varela, Melanie [1 ,2 ]
Filippova, Maria [1 ,3 ]
Linkhart, Thomas A. [5 ]
Gijsbers, Rik [7 ]
Debyser, Zeger [7 ]
Casiano, Carlos A. [1 ,2 ,4 ]
机构
[1] Loma Linda Univ, Sch Med, Ctr Hlth Disparit & Mol Med, Loma Linda, CA 92350 USA
[2] Loma Linda Univ, Sch Med, Div Microbiol & Mol Genet, Loma Linda, CA 92350 USA
[3] Loma Linda Univ, Sch Med, Div Biochem, Loma Linda, CA 92350 USA
[4] Loma Linda Univ, Sch Med, Dept Med, Loma Linda, CA 92350 USA
[5] Jerry L Pettis Mem Vet Affairs Med Ctr, Muskuloskeletal Dis Ctr, Loma Linda, CA USA
[6] Ctr Univ Adventista Sao Paulo, Dept Biol Sci, Sao Paulo, Brazil
[7] Katholieke Univ Leuven, B-3000 Louvain, Belgium
关键词
D O I
10.1158/1541-7786.MCR-08-0125
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
There is increasing evidence that an augmented state of cellular oxidative stress modulates the expression of stress genes implicated in diseases associated with health disparities such as certain cancers and diabetes. Lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 autoantigen, is emerging as a survival oncoprotein that promotes resistance to oxidative stress-induced cell death and chemotherapy. We previously showed that LEDGF/p75 is targeted by autoantibodies in prostate cancer patients and is overexpressed in prostate tumors, and that its stress survival activity is abrogated during apoptosis. LEDGF/p75 has a COOH-terminally truncated splice variant, p52, whose role in stress survival and apoptosis has not been thoroughly investigated. We observed unbalanced expression of these proteins in a panel of tumor cell lines, with LEDGF/p75 generally expressed at higher levels. During apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the NH2-terminal PWWP domain and failed to transactivate the Hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of LEDGF/p75. Overexpression of p52 or its variants with truncated PWWP domains in several tumor cell lines induced apoptosis, an activity that was linked to the presence of an intron-derived COOH-terminal sequence. These results implicate the PWWP domain of p52 in transcription function but not in chromatin association and proapoptotic activities. Consistent with their unbalanced expression in tumor cells, LEDGF/p75 and p52 seem to play antagonistic roles in the cellular stress response and could serve as targets for novel antitumor therapies.
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页码:1293 / 1307
页数:15
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