Ec. Thornborrow et Jj. Manfredi, One mechanism for cell type-specific regulation of the bax promoter by thetumor suppressor p53 is dictated by the p53 response element, J BIOL CHEM, 274(47), 1999, pp. 33747-33756
Key to the function of the tumor suppressor p53 is its ability to activate
the transcription of its target genes, including those that encode the cycl
in-dependent kinase inhibitor p21 and the proapoptotic Bar protein. In cont
rast to Saos-2 cells in which p53 activated both the p21 and bar promoters,
in MDA-MB-453 cells p53 activated the p21 promoter, but failed to activate
the bar promoter. Neither phosphorylation of p53 on serines 315 or 392 nor
an intact C terminus was required for p53-dependent activation of the bax
promoter, demonstrating that this differential regulation of bax could not
be explained solely by modifications of these residues. Further, this effec
t was not due to either p73 or other identified cellular factors competing
with p53 for binding to its response element in the bar promoter. p53 expre
ssed in MDA-MB-453 cells also failed to activate transcription through the
p53 response element of the bar promoter in isolation, demonstrating that t
he defect is at the level of the interaction between p53 and its response e
lement. In contrast to other p53 target genes, like p21, in which p53-depen
dent transcriptional activation is mediated by a response element containin
g two consensus p53 half-sites, activation by p53 of the bax element was me
diated by a cooperative interaction of three adjacent half-sites. In additi
on, the interaction of p53 with its response element from the bax promoter,
as compared with its interaction with its element from the p21 promoter, i
nvolves a conformationally distinct form of the protein. Together, these da
ta suggest a potential mechanism for the differential regulation of p53-dep
endent transactivation of the bar and p21 genes.