title: p73 independent of c-Myc represses transcription of platelet-derived growth factor beta-receptor through interaction with NF-Y.
abstract: We recently reported that c-Myc represses the transcription of platelet-derived growth factor (PDGF) beta-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 p73alpha represses PDGF beta-receptor transcription essentially by the same mechanism. p73alpha but not p73beta or p53 represses the transcription in concordance with its ability to bind NF-YC and NF-YB. None of other p73 isoforms (i.e. p73beta, p73gamma, p73epsilon), C-terminal deletion mutants of p73alpha, and p53 is able to bind NF-Y with the exception of p63alpha. This finding suggests that the sterile alpha-motif domain present only in p73alpha and p63alpha is the interaction site. For the repression, the N-terminal transactivation domain of p73alpha is also indispensable, arguing for the importance of the activity of p73alpha in the mechanism. p73alpha 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 p73alpha (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 p73alpha-induced repression. Serum stimulation of NIH3T3 cells gradually decreased the amount of endogenous NF-Y binding to the PDGF beta-receptor promoter, whereas NF-YA expression in the nuclear extracts remains unchanged. Our results indicate that serum stimulation induces c-Myc and p73alpha, leading to the down-regulation of PDGF beta-receptor expression by repressing its transcription.
authors.affiliation: Department of Cell Biology, Institute of Anatomy and Cell Biology, Göteborg University, Box 420, SE-405 30 Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hackzell
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uramoto
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
authors.forename: Keiko
authors.initials: K
authors.lastname: Funa
mesh_terms: D016475:3T3 Cells; D020816:Amino Acid Motifs; D000818:Animals; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors; D015151:Immunoblotting; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques
chemical_list: D023081:CCAAT-Binding Factor; D004268:DNA-Binding Proteins; C469358:NFYC protein, human; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; C000606460:TP73 protein, human; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta