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Caspase cleavage of transcription factor Sp1 enhances apoptosis

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Abstract

Sp1 is a ubiquitous transcription factor that regulates many genes involved in apoptosis and senescence. Sp1 also has a role in the DNA damage response; at low levels of DNA damage, Sp1 is phosphorylated by ATM and localizes to double-strand break sites where it facilitates DNA double-strand-break repair. Depletion of Sp1 increases the sensitivity of cells to DNA damage, whereas overexpression of Sp1 can drive cells into apoptosis. In response to a variety of stimuli, Sp1 can be regulated through proteolytic cleavage by caspases and/or degradation. Here, we show that activation of apoptosis through DNA damage or TRAIL-mediated activation of the extrinsic apoptotic pathway induces caspase-mediated cleavage of Sp1. Cleavage of Sp1 was coincident with the appearance of cleaved caspase 3, and produced a 70 kDa Sp1 product. In vitro analysis revealed a novel caspase cleavage site at aspartic acid 183. Mutation of aspartic acid 183 to alanine conferred resistance to cleavage, and ectopic expression of the Sp1 D183A rendered cells resistant to apoptotic stimuli, indicating that Sp1 cleavage is involved in the induction of apoptosis. The 70 kDa product resulting from caspase cleavage of Sp1 comprises amino acids 184–785. This truncated form, designated Sp1-70C, which retains transcriptional activity, induced apoptosis when overexpressed in normal epithelial cells, whereas Sp1D183A induced significantly less apoptosis. Together, these data reveal a new caspase cleavage site in Sp1 and demonstrate for the first time that caspase cleavage of Sp1 promotes apoptosis.

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This study was funded by College of Medicine, Drexel University.

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  1. Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA

    Behzad Torabi, Samuel Flashner, Kate Beishline, Aislinn Sowash, Kelly Donovan, Garrett Bassett & Jane Azizkhan-Clifford

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  1. Behzad Torabi
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  2. Samuel Flashner
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Correspondence to Jane Azizkhan-Clifford.

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Torabi, B., Flashner, S., Beishline, K. et al. Caspase cleavage of transcription factor Sp1 enhances apoptosis. Apoptosis 23, 65–78 (2018). https://doi.org/10.1007/s10495-017-1437-4

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