Hsp72 mediates TAp73α anti-apoptotic effects in small cell lung carcinoma cells

被引:6
|
作者
Nyman, Ulrika [1 ]
Muppani, Naveen Reddy [1 ]
Zhivotovsky, Boris [2 ]
Joseph, Bertrand [1 ]
机构
[1] Karolinska Inst, Canc Centrum Karolinska, Dept Oncol Pathol, SE-17176 Stockholm, Sweden
[2] Karolinska Inst, Inst Environm Med, SE-17176 Stockholm, Sweden
基金
瑞典研究理事会;
关键词
p73; alpha; hsp72; HSPA1A; apoptosis; mitochondria; Bax; LYSOSOMAL MEMBRANE PERMEABILIZATION; STRESS-INDUCED APOPTOSIS; HUMAN BLADDER-CANCER; HEAT-SHOCK PROTEINS; WILD-TYPE P73; TUMOR-SUPPRESSOR; P53-RELATED PROTEIN; EXPRESSION; P53; P73-ALPHA;
D O I
10.1111/j.1582-4934.2010.01166.x
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The transcription factor p73, a member of the p53 family of proteins, is involved in the regulation of cell cycle progression and apoptosis. Due to alternative promoters and carboxy-terminal splicing, the P73 gene gives rise to a range of different isoforms. Interestingly, a particular increase in expression of the TAp73 alpha isoform has been reported in various tumours. In addition, TAp73 alpha has been shown to inhibit Bax activation and mitochondrial dysfunctions and thereby to confer small cell lung carcinoma (SCLC) cells resistance to drug-induced apoptosis. However, the precise mechanism by which TAp73 alpha exerts its pro-survival effect is yet unclear. Here we report that TAp73 alpha, but not TAp73 alpha, regulates the expression of inducible Hsp72/HSPA1A. Hsp72 proved to be required for the survival effects of TAp73 alpha as antisense knockdown of Hsp72 resulted in an abolishment of the anti-apoptotic effect of TAp73 alpha in SCLC cells upon Etoposide treatment. Importantly, depletion of Hsp72 allowed activation of Bax, loss of mitochondrial membrane potential and lysosomal membrane permeabilization in SCLC cells even in the presence of TAp73 alpha. Finally, we revealed that TAp73 alpha counteracts the antiapoptotic effect of TAp73 alpha by preventing Hsp72 induction. Our results thus provide additional evidence for the potential oncogenic role of TAp73 alpha, and extend the understanding of the mechanism for its anti-apoptotic effect.
引用
收藏
页码:1757 / 1768
页数:12
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