REGULATION OF INSULIN-LIKE-GROWTH-FACTOR-II P3 PROMOTER BY P53 - A POTENTIAL MECHANISM FOR TUMORIGENESIS

Human insulin-like growth factor (IGF)-II mRNA has been shown to be ex pressed at high levels in a variety of tumors, including rhabdomyosarc omas, In addition, many tumors have alterations in p53 expression. To investigate whether p53 regulates IGF-II gene expression, we transfect ed wild-type p53 expression vectors and luciferase constructs driven b y IGF-II P3 promoters into multiple cell lines. We found that p53 redu ced, in a dose-dependent manner, both endogenous IGF-II P3 transcripts and transfected P3 luciferase expression. The inhibition of P3 lucife rase expression by p53 was more pronounced in the two cell lines that expressed mutant p53 protein, RD, and HTB114. The element responsible for this inhibition was mapped to the minimal promoter region. We also transfected an HPV-16 E6 expression plasmid into CCL13 cells containi ng functional p53 and found that E6 up-regulated IGF-II P3 activity. W ildtype, but not mutant, p53 interfered with the binding of TATA-bindi ng protein to the TATA motif of P3, although both could directly assoc iate with human TATA-binding protein. Our results suggest that p53 may play a role in regulation of IGF-II gene expression.