P73 expression modulates p63 and Mdm2 protein presence in complex with p53 family-specific DNA target sequence in squamous cell carcinogenesis

作者：Johnson J; Lagowski J; Lawson S; Liu Y; Kulesz Martin M^*

来源：Oncogene, 2008, 27(19): 2780-2787.

DOI：10.1038/sj.onc.1210941

• p73
• squamous cell carcinoma
• keratinocyte
• p53 family interplay

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 Delta Np63 alpha isoform and reduction of transcriptionally active p63 gamma isoforms binding to a p21 promoter sequence in vitro. Reconstitution of TAp73 alpha in malignant cells increased the steady state DNA-binding capabilities of the endogenous transcriptionally active TAp63 gamma and Delta Np63 gamma 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 alpha expression resulted in exclusion of Mdm2 from these complexes. These results suggest a dual mechanism for TAp73 alpha to foster tumor suppression through enhancement of the DNA-binding activity of p63 gamma isoforms, and through inhibition of transcriptional repressors Mdm2 or DNp63a.

• 出版日期2008-4-24