1. ¹Department of Dermatology, Oregon Health & Science University, Portland, OR, USA
2. ²Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA
3. ³Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, OR, USA

Correspondence: Dr M Kulesz-Martin, Department of Dermatology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. E-mail: kuleszma@ohsu.edu

Received 16 August 2007; Revised 28 September 2007; Accepted 16 October 2007; Published online 19 November 2007.

Abstract

The expression of p73 and p63 isoforms is frequently deregulated in human epithelial tumors. We previously showed that loss of p73 protein expression associates with malignant conversion in vivo and ionizing radiation (IR) resistance in vitro in a clonal model of mouse epidermal carcinogenesis. Here we show that loss of endogenous p73 expression in squamous cell carcinoma (SCC) cells and tumors was concomitant with preferential DNA binding of the inhibitory Np63 isoform and reduction of transcriptionally active p63 isoforms binding to a p21 promoter sequence in vitro. Reconstitution of TAp73 in malignant cells increased the steady state DNA-binding capabilities of the endogenous transcriptionally active TAp63 and Np63 isoforms, correlating with restoration of tumor suppression but not IR sensitivity. Loss of p73 in malignant cells also coincided with increased presence of p53 family inhibitor Mdm2 in p53-specific DNA-bound complexes, whereas reconstitution of TAp73 expression resulted in exclusion of Mdm2 from these complexes. These results suggest a dual mechanism for TAp73 to foster tumor suppression through enhancement of the DNA-binding activity of p63 isoforms, and through inhibition of transcriptional repressors Mdm2 or Np63.