Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells.
The tumor suppressor gene p53 is known to induce G1-S and G2-M cell cycle arrest and apoptosis by transactivating various wild-type (WT) p53 regulatory genes. Mutational inactivation of p53 is detected in more than half of human cancers, depriving the p53 protein of its tumor-suppressive functions. Recent studies have shown that mutant p53 provides tumor cells with gain-of-function properties, such as accelerated cell proliferation, increased metastasis, and apoptosis resistance. However, the mechanism underlying the elevated tumorigenicity by p53 mutation remains to be elucidated. In the present study, we showed that GEF-H1, a guanine exchange factor-H1 for RhoA, is transcriptionally activated by the induction of mutant p53 proteins, thereby accelerating tumor cell proliferation. Osteosarcoma U2OS cell lines, which express inducible p53 mutants (V157F, R175H, and R248Q), were established, and the expression profiles of each cell line were then analyzed to detect genes specifically induced by mutant p53. We identified GEF-H1 as one of the consensus genes whose expression was significantly induced by the three mutants. The GEF-H1 expression level strongly correlated with p53 status in a panel of 32 cancer cell lines, and GEF-H1 induction caused activation of RhoA. Furthermore, growth of mutant p53 cells was dependent on GEF-H1 expression, whereas that of WT p53 cells was not. These results suggest that increased GEF-H1 expression contributes to the tumor progression phenotype associated with the p53 mutation.
Mizuarai
Shinji
S
Functional Genomics, Banyu Tsukuba Research Institute, Merck Research Laboratory, Tsukuba, Ibaraki, Japan.
Yamanaka
Kazunori
K
Kotani
Hidehito
H
D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D009154:Mutation; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064067:Rho Guanine Nucleotide Exchange Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C577356:ARHGEF2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D020742:rhoA GTP-Binding Protein