The role of transcription factor SP1 in apoptosis

Behzad Torabi

doi:10.17918/00010175

Sp1 is a ubiquitous transcription factor that regulates many genes involved in cellular proliferation, cell cycle, DNA damage, apoptosis and senescence. Earlier work in this lab demonstrated that Sp1 is phosphorylated by ATM kinase in response to DNA damage. At high levels of DNA damage, Sp1 was observed to be degraded. This work was directed at determining the mechanism and significance of Sp1 degradation. High levels of DNA damage or activation of the extrinsic apoptotic pathway by TRAIL, resulted in caspase-mediated cleavage of Sp1. Further analysis revealed that caspase cleavage of Sp1 in cell free or cell systems is at aspartic acid 183, a site which has not been shown previously to be targeted by caspases. Sp1 with mutation at residue 183 from aspartic acid to alanine is resistant to cleavage, and ectopic expression of Sp1 D183A renders cells resistant to apoptotic stimuli, indicating that Sp1 cleavage is involved in the induction of apoptosis. We also observed that lowering levels of transcription factor Sp1 with RNAi significantly reduces apoptosis in response to various apoptotic stimuli. Whether these effects were due modulation of transcription of factors involved in apoptosis was further explored. We have identified pro-apoptotic Bd-2 family member Bid as a transcriptional target of Sp1. Depletion of Sp1 by RNAi significantly reduced levels of Bid protein and mRNA, whereas, over-expression of Sp1 increased Bid RNA and protein levels. We used chromatin immunoprecipitation to demonstrate that Sp1 binds to the BID promoter in the same region previously shown to be bound by p53. The regulation of Bid by Sp1 is p53 independent, based on the finding that Bid was induced by Sp1 over-expression in SAOS-2 cells, which are p53-/-; moreover, the depletion of Sp1 had no effect on p53 levels. Knockdown of SO or Bid significantly reduced apoptosis in response to UV and TRAIL. Taken together, these findings suggest that Sp1 is involved in regulation of apoptosis through caspase-mediated cleavage and transcriptional regulation of Bid. Many traditional chemotherapies and new therapeutic approaches target apoptosis initiation. The regulation of Bid and apoptosis by SO may provide a therapeutic target for cancer therapy.

The role of transcription factor SP1 in apoptosis

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The role of transcription factor SP1 in apoptosis

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