Jh. Ludesmeyers et al., TRANSCRIPTIONAL ACTIVATION OF THE HUMAN EPIDERMAL GROWTH-FACTOR RECEPTOR PROMOTER BY HUMAN P53, Molecular and cellular biology, 16(11), 1996, pp. 6009-6019
The human epidermal growth factor receptor (EGFR) promoter is activate
d by both wild-type and tumor-derived mutant p53. In this communicatio
n, we demonstrate that EGFR promoter sequence requirements for transac
tivation by wild-type and mutant p53 are different. Transient-expressi
on assays with EGFR promoter deletions identified a wild-type human p5
3 response element, 5'-AGCTAGACGTCCGGGCAGCCCCCGGCG -3', from positions
-265 to -239. Electrophoretic mobility shift analysis and DNase I foo
tprinting assays indicated that wild-type p53 binds sequence specifica
lly to the response element. Using circularly permuted DNA fragments c
ontaining the p53-binding site, we show that wild-type p53 binding ind
uces DNA bending at this site. We further show that the EGFR promoter
is also activated by tumor-derived p53 mutants p53-143A, p53-175H, p53
-248W, p53-273H, and p53-281G. However, the transactivation by mutant
p53 does not require the wild-type p53-binding site. The minimal EGFR
promoter from positions -104 to -20 which does not contain the wild-ty
pe p53-binding site is transactivated by the p53 mutants but not by th
e wild-type protein, showing a difference in the mechanism of transact
ivation by wild-type and mutant p53. Transactivation of the EGFR promo
ter by p53 may represent a novel mechanism of cell growth regulation.