The Phosphotyrosyl Phosphatase Activator Gene Is a Novel p53
Target Gene*
Veerle
Janssens,
Christine
Van Hoof
,
Ivo
De Baere,
Wilfried
Merlevede, and
Jozef
Goris§
From the Afdeling Biochemie, Faculteit Geneeskunde, Katholieke
Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium
The minimal promoter of the phosphotyrosyl
phosphatase activator (PTPA) gene, encoding a regulator of protein
phosphatase 2A contains two yin-yang 1 (YY1)-binding sites, positively
regulating promoter activity. We now describe a role for p53 in the
regulation of PTPA expression. Luciferase reporter assays
in Saos-2 cells revealed that p53 could down-regulate PTPA
promoter activity in a dose-dependent manner, whereas four
different p53 mutants could not. The p53-responsive region mapped to
the minimal promoter. Overexpression of YY1 reverses the repressive
effect of p53, suggesting a functional antagonism between p53 and YY1.
The latter does not involve competition for YY1 binding, but rather
direct control of YY1 function. Inhibition of PTPA
expression by endogenous p53 was demonstrated in UVB-irradiated HepG2
cells, both on the mRNA and protein level. Also basal PTPA levels
are higher in p53-negative (Saos-2) versus p53-positive
(HepG2, U2OS) cells, suggesting "latent" p53 can control
PTPA expression as well. The higher PTPA levels in U2OS
cells, programmed to overexpress constitutively a dominant-negative p53
mutant, corroborate this finding. Thus, PTPA expression is negatively regulated by p53 in normal conditions and in conditions where p53 is up-regulated, via an as yet unknown mechanism involving the negative control of YY1.
*
This work was supported in part by grants from the "Fonds
voor Wetenschappelijk Onderzoek-Vlaanderen," "Geconcerteerde
OnderzoekActies" (GOA) van de Vlaamse Gemeenschap, Human Frontier
Science Program, and the European Community Biomed2 Cancer Research
Program.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.