Transcriptional dysregulation of the p73L/p63/p51/p40/KET gene in human squamous cell carcinomas: expression of Delta Np73L, a novel dominant-negative isoform, and loss of expression of the potential tumour suppressor p51

We have recently identified a second p53-related p73L gene, also referred t o as p63/p51/p40/KET gene, which encodes the 2 major isoforms p73L and p51 resulting from different exon usage at their amino terminal regions. Althou gh p73L and p51 are suspected to play oncogenic and tumour suppressive role s in mammalian cells, respectively, no evidence of linkage between the expr ession of these isoforms and human cancers has been reported so far. In thi s study, we first investigated the expression profile of p51 and p73L in va rious human tumour cell lines and found that a novel isoform, termed Delta Np73L, was predominantly expressed in squamous cell carcinomas. The express ion profile of Delta Np73L/p73L/p51 in primary human skin cancer specimens showed that the expression of p51 was frequently lost (62%) but was detecte d in all normal skin samples. In p51-expressing skin cancers, Delta Np73L e xpression was associated at a high frequency (75%) though it was not detect ed in normal skin tissues. Transient co-transfection data indicate the poss ibility that Delta Np73L can inhibit p53-, and more preferentially, p51-med iated transactivation. These data suggest that the loss of expression of p5 1 and/or the expression of Delta Np73L might contribute to the pathogenesis of human squamous cell carcinomas. (C) 2001 Cancer Research Campaign.