A naturally occurring p73 mutation in a p73-p53 double-mutant lung cancer cell line encodes p73 alpha protein with a dominant-negative function.
p73, a close homolog of p53 tumor suppressor, induces growth arrest and apoptosis. However, its role in cancers is controversial because of the rarity of p73 mutations, lack of tumors in p73-knockout mice, and the presence of multiple isotypes, among which Delta N isotypes inhibit the function of TA isotypes. We analyzed three naturally occurring p73 mutants found in lung cancer cell lines, NCI-H1155, DMS 92 and A427. NCI-H1155 is a cell line that has a p73 mutation [p73(G264W)] in the DNA-binding domain, as well as a p53 mutation [p53(R273H)], which is frequently found in human cancers and has a "gain-of-function" characteristic. p73 alpha(G264W) not only lacks transactivation activity itself, but also suppressed the transactivation activity of the wild-type p73 alpha in a dose-dependent manner, indicating that p73 alpha(G264W) is a dominant-negative mutant. p73 alpha(G264W) failed to suppress colony formation. We tested two other mutations, p73(Del418) in DMS 92 and p73(Del603) in A427. Both mutants retained similar levels of transactivation activity and suppression of colony formation to those of wild-type p73. The biological significance of these two mutations is unclear. In NCI-H1155 cells the coexistence of mutations that abrogate the normal functions of p73 and p53 may indicate that each mutation confers an additive growth advantage upon the cells.
Huqun
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai 980-8575, Japan.
Endo
Yoshiyuki
Y
Xin
Hong
H
Takahashi
Mitsu
M
Nukiwa
Toshihiro
T
Hagiwara
Koichi
K
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins