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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

3T3 Cells

Amino Acid Motifs

Animals

CCAAT-Binding Factor

metabolism

COS Cells

DNA-Binding Proteins

metabolism

Down-Regulation

Fibroblasts

metabolism

Gene Deletion

Genes

Reporter

Genes

Tumor Suppressor

Genetic Vectors

Immunoblotting

Mice

Nuclear Proteins

metabolism

Oligonucleotides

Antisense

pharmacology

Promoter Regions

Genetic

Protein Binding

Protein Structure

Tertiary

Proto-Oncogene Proteins c-myc

metabolism

Rats

Receptor

Platelet-Derived Growth Factor beta

metabolism

Recombinant Fusion Proteins

metabolism

Reverse Transcriptase Polymerase Chain Reaction

Time Factors

Transcription Factors

metabolism

Transcription

Genetic

Transcriptional Activation

Transfection

Tumor Protein p73

Tumor Suppressor Protein p53

metabolism

Tumor Suppressor Proteins

Two-Hybrid System Techniques

Publikations- och innehållstyp

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