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Molecular and Cellular Biology, December 2001, p. 8461-8470, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8461-8470.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Transcriptional Repressor ZEB Regulates p73 Expression at the Crossroad between Proliferation and Differentiation†

Giulia Fontemaggi,1 Aymone Gurtner,1 Sabrina Strano,1 Yujiro Higashi,2 Ada Sacchi,1 Giulia Piaggio,1 and Giovanni Blandino1,*

Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, 00158 Rome, Italy,1 and Institute for Molecular and Cellular Biology, Osaka University, Osaka 565-0871, Japan2

Received 27 July 2001/Returned for modification 4 September 2001/Accepted 25 September 2001

The newly discovered p73 gene encodes a nuclear protein that has high homology with p53. Furthermore, ectopic expression of p73 in p53+/+ and p53-/- cancer cells recapitulates some of the biological activities of p53 such as growth arrest, apoptosis, and differentiation. p73-/--deficient mice exhibit severe defects in proper development of the central nervous system and pheromone sensory pathway. They also suffer from inflammation and infections. Here we studied the transcriptional regulation of p73 at the crossroad between proliferation and differentiation. p73 mRNA is undetectable in proliferating C2C12 cells and is expressed at very low levels in undifferentiated P19 and HL60 cells. Conversely, it is upregulated during muscle and neuronal differentiation as well as in response to tetradecanoyl phorbol acetate-induced monocytic differentiation of HL60 cells. We identified a 1-kb regulatory fragment located within the first intron of p73, which is positioned immediately upstream to the ATG codon of the second exon. This fragment exerts silencer activity on p73 as well as on heterologous promoters. The p73 intronic fragment contains six consensus binding sites for transcriptional repressor ZEB, which binds these sites in vitro and in vivo. Ectopic expression of dominant-negative ZEB (ZEB-DB) restores p73 expression in proliferating C2C12 and P19 cells. Thus, transcriptional repression of p73 expression by ZEB binding may contribute to the modulation of p73 expression during differentiation.

* Corresponding author. Mailing address: Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro, 156, 00158 Rome, Italy. Phone: 39-06-52662563. Fax: 39-06-4180526. E-mail: blandino{at}ifo.it.

dagger This work is dedicated to the memory of F. Tatò.

Molecular and Cellular Biology, December 2001, p. 8461-8470, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8461-8470.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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