p53 associates with and targets Delta Np63 into a protein degradation pathway.
A human p53 homologue, p63 (p40/p51/p73L/CUSP) that maps to the chromosomal region 3q27-29 was found to produce a variety of transcripts that encode DNA-binding proteins with and without a trans-activation domain (TA- or Delta N-, respectively). The p63 gene locus was found to be amplified in squamous cell carcinoma, and overexpression of Delta Np63 (p40) led to increased growth of transformed cells in vitro and in vivo. Moreover, p63-null mice displayed abnormal epithelial development and germ-line human mutations were found to cause ectodermal dysplasia. We now demonstrate that certain p63 isotypes form complexes with p53. p53 mutations R175H or R248W abolish the association of p53 with p63, whereas V143A or R273H has no effect. Deletion studies suggest that the DNA-binding domains of both p53 and p63 mediate the association. Overexpression of wild type but not mutant (R175H) p53 results in the caspase-dependent degradation of certain Delta Np63 proteins (p40 and Delta Np63 alpha). The association between p53 and Delta Np63 supports a previously unrecognized role for p53 in regulation of Delta Np63 stability. The ability of p53 to mediate Delta Np63 degradation may balance the capacity of Delta Np63 to accelerate tumorigenesis or to induce epithelial proliferation.
Ratovitski
E A
EA
Department of Otolaryngology-Head and Neck Surgery, Division of Head and Neck Cancer Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. erat@welch.jhu.edu
Patturajan
M
M
Hibi
K
K
Trink
B
B
Yamaguchi
K
K
Sidransky
D
D
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins; D012441:Saccharomyces cerevisiae; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; C077214:L1Hs-encoded protein p40, human