Hsp72 mediates TAp73α anti-apoptotic effects in small cell lung carcinoma cells.
Bottom Line: However, the precise mechanism by which TAp73α exerts its pro-survival effect is yet unclear.Finally, we revealed that TAp73β counteracts the anti-apoptotic effect of TAp73α by preventing Hsp72 induction.Our results thus provide additional evidence for the potential oncogenic role of TAp73α, and extend the understanding of the mechanism for its anti-apoptotic effect.
Affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.Show MeSH
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Mentions: It is known since before that the p73 isoforms can interact and regulate the activity of each other [16, 29]. Given that TAp73α is able to transactivate the HSP72 promoter (Fig. 1), we decided to investigate whether TAp73β could affect the activity of TAp73α with regards to the HSP72 promoter. Subsequently, H82 cells were transfected with HSP72-luciferase construct, TAp73α and increasing amounts of TAp73β. In a dose-dependent manner, TAp73β was able to significantly reduce the level of transactivation of TAp73α on the HSP72 promoter (Fig. 7A). Using chromatin immunoprecipitation assay and primers covering a region of the promoter including a p53 responsive element, we show that TAp73α directly binds to the HSP72 promoter, whereas TAp73β do not (Fig. 7B). Consequently, to investigate if this effect was reflected on the outcome of apoptosis, H82 cells were transfected with TAp73α and increasing amounts of TAp73β, and treated with VP16. Indeed, in a dose-dependent manner TAp73β was able to reverse the anti-apoptotic effect of TAp73α on drug-induced apoptosis (Fig. 7C). Thus, the Hsp72-dependent anti-apoptotic effect of TAp73α can be counteracted by simultaneous co-expression of TAp73β.
Affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.