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Differential regulation of the pro-apoptotic multidomain protein Bak by p53 and p73 at the promoter level

Abstract : During apoptosis, Bcl-2 proteins control permeabilization of the mitochondrial outer membrane leading to the release of cytochrome c. Essential gate keepers for the cytochrome c release are the pro-apoptotic multidomain proteins, Bax and/or Bak. The expression of bax is upregulated upon cellular stress by the tumor suppressor p53. Despite the high functional homology of Bax and Bak little is known about how the bak gene is regulated. To investigate its transcriptional regulation in further detail, we have analyzed a region spanning 8200 bp upstream of the bak start codon (within exon 2) for transcription factor binding sites and identified three p53 consensus sites (BS1-3). Reporter gene assays in combination with site-directed mutagenesis revealed that only one putative p53-binding site (BS3) is necessary and sufficient for induction of reporter gene expression by p53. Consistently, p53 induces expression of endogenous bak. At the mRNA level, induction of bak expression is weaker than induction of puma and p21. Interestingly, Bak expression can also be induced by p73 that binds however to each of the three p53 binding sites within the bak promoter region. Our data suggest that expression of bak can be induced by both, p53 and p73 utilizing different binding sites within the bak promoter.
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Submitted on : Thursday, July 14, 2011 - 2:52:40 AM
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Klaus Schulze-Osthoff, Vilma Graupner, Eva Alexander, Oliver Rothfuss, Tim Overkamp, et al.. Differential regulation of the pro-apoptotic multidomain protein Bak by p53 and p73 at the promoter level. Cell Death and Differentiation, Nature Publishing Group, 2011, ⟨10.1038/cdd.2010.179⟩. ⟨hal-00608717⟩

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