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Sp1‐like sequences mediate human caspase‐3 promoter activation by p73 and cisplatin
Author(s) -
Sudhakar Cherukuri,
Jain Nishant,
Swarup Ghanshyam
Publication year - 2008
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2008.06373.x
Subject(s) - cisplatin , cancer research , chemistry , caspase , microbiology and biotechnology , apoptosis , computational biology , biology , genetics , biochemistry , programmed cell death , chemotherapy
Caspase‐3 is a cysteine protease that plays a central role in the execution of apoptosis induced by a wide variety of stimuli. However, little is known about the mechanisms involved in the regulation of caspase‐3 gene transcription. This study was carried out to characterize the human caspase‐3 promoter and to understand the mechanisms involved in the induction of caspase‐3 gene expression in response to the anticancer drug cisplatin and p73. Caspase‐3 gene expression was induced by treatment of cells with cisplatin, which also induced p73 protein in HeLa and K562 cells. The human caspase‐3 promoter was cloned and characterized. p73β strongly activated the caspase‐3 promoter, whereas p73α showed less activation. Cisplatin treatment increased caspase‐3 promoter activity. Basal and cisplatin‐induced promoter activity was inhibited by the p73 inhibitor p73DD. Deletion analysis defined a minimal promoter of 120 base pairs, which showed good basal and p73β‐induced activity. The examination of the minimal promoter sequence showed several putative Sp1 sites, but no p53/p73 site. The caspase‐3 promoter was activated by Sp1 in Sp1‐deficient Drosophila SL‐2 cells. Sp1‐induced promoter activity was further enhanced by p73β in SL‐2 cells. Mutation of Sp1 sites in the minimal promoter resulted in a loss of basal and p73‐induced promoter activity. These results show that caspase‐3 gene transcription is induced by cisplatin, which is mediated partly by p73. We have identified p73 and Sp1 as activators of the caspase‐3 promoter. Sp1‐like sequences in the minimal promoter not only sustain basal promoter activity, but also mediate p73‐induced activation of the promoter.