p73 independent of c-Myc represses transcription of platelet-derived growth factor β-receptor through interaction with NF-Y

Abstract

We recently reported that c-Myc represses the transcription of platelet-derived growth factor (PDGF) β-receptor (Izumi, H., Molander, C., Penn, L. Z., Ishisaki, A., Kohno, K., and Funa, K. (2001) J. Cell Sci. 114, 1533-1544). We demonstrate here that the p53 family protein p73α represses PDGF β-receptor transcription essentially by the same mechanism. p73α but not p73β or p53 represses the transcription in concordance with its ability to bind NF-YC and NF-YB. None of other p73 isoforms (i.e. p73β, p73γ, p73ε), C-terminal deletion mutants of p73α, and p53 is able to bind NF-Y with the exception of p63α. This finding suggests that the sterile α-motif domain present only in p73α and p63α is the interaction site. For the repression, the N-terminal transactivation domain of p73α is also indispensable, arguing for the importance of the activity of p73α in the mechanism. p73α binds the C-terminal HAP domain of NF-YC previously found to be the interaction site with c-Myc and TBP. Because c-Myc induces and activates p73α (Zaika, A., Irwin, M., Sansome, C., and Moll, U. M. (2001) J. Biol. Chem. 276, 11310-11316) and they bind each other (Uramoto, H., Izumi, H., Ise, T., Tada, M., Uchiumi, T., Kuwano, M., Yasumoto, K., Funa, K., and Kohno, K. (2002) J. Biol. Chem. 277, in press), we examined whether the repression by p73 is dependent on c-Myc. However, Myc-null rat fibroblasts are also susceptible to p73α-induced repression. Serum stimulation of NIH3T3 cells gradually decreased the amount of endogenous NF-Y binding to the PDGF β-receptor promoter, whereas NF-YA expression in the nuclear extracts remains unchanged. Our results indicate that serum stimulation induces c-Myc and p73α, leading to the down-regulation of PDGF β-receptor expression by repressing its transcription.