1. ¹Department of Experimental Oncology, Regina Elena Cancer Institute, Rome, Italy
2. ²Rome Oncogenomic Center, Rome, Italy
3. ³Department of Pediatric Hematology-Oncology, Sheba Medical Center, Tel-Hashomer, Israel
4. ⁴Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

Correspondence: Dr G Blandino, Department of Experimental Oncology, Regina Elena Cancer Institute, Molecular Oncogenesis Laboratory, Via delle Messi d' oro, 156, Rome RM 158, Italy. E-mail: blandino@ifo.it

⁵These two authors contributed equally to this work.

Received 14 June 2005; Revised 19 December 2005; Accepted 19 December 2005; Published online 30 January 2006.

Abstract

The p53 paralogues p73, p63 and their respective truncated isoforms have been shown to be critical regulators of developmental and differentiation processes. Indeed, both p73- and p63-deficient mice exhibit severe developmental defects. Here, we show that S100A2 gene, whose transcript and protein are induced during keratinocyte differentiation of HaCaT cells, is a direct transcriptional target of p73 and Np63 and is required for proper keratinocyte differentiation. Transactivation assays reveal that p73 and Np63 exert opposite transcriptional effects on S100A2 gene. While Np63 is found in vivo onto S100A2 regulatory regions predominantly in proliferating cells, p73 is recruited in differentiating cells. Silencing of p73 impairs the induction of S100A2 during the differentiation of HaCaT cells. Moreover, silencing of p73 or S100A2 impairs the proper expression of keratinocyte differentiation markers. Of note, p53 family members do not trigger S100A2 gene expression in response to apoptotic doses of cisplatin and doxorubicin.