Abstract
The novel candidate tumor suppressor p73, a structural and functional homolog of p53, activates various p53 responsive promoters and induces tumor cell apoptosis. Although p73 is infrequently mutated in human cancers, we have previously found two types of p73 mutation with amino acid substitution (P405R and P425L) in primary neuroblastoma and lung cancer. Here we report generations of the p73 mutants with either P405R or P425L substitution and functional analysis of these naturally occurring mutants. Indirect immunofluorescence staining revealed that nuclear accumulation of p73α or p73β was not affected by these mutations. The P425L substitution reduced the ability of p73α to transactivate various p53 responsive promoters (p21Waf1, Mdm2, and Bax). Moreover, this down-regulation was correlated with the reduced capability of p73α(P425L) to suppress cell growth in p53-deficient SAOS-2 cells. In contrast, p73β(P425L) was as effective as wild-type p73β in transactivation and growth inhibition. On the other hand, the P405R substitution had no significant effect on both the transcriptional activity and the growth-suppressive ability of p73α or p73β. These results suggested that, at least, one of the naturally occurring p73 mutants, p73α(P425L), was a functionally defective mutant of p73.
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Acknowledgements
We are grateful to Dr Gerry Melino (University of Rome, Rome, Italy) for providing the mammalian expression plasmid encoding HA epitope-tagged p73α, p73β or p73γ. We thank Aiko Morohashi for her technical assistance. This work was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for a New 10-Year Strategy for Cancer Control, a Grant-in-Aid for Scientific Research on Priority Areas, and a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Science, Sports and Culture, Japan.
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Naka, M., Ozaki, T., Takada, N. et al. Functional characterization of naturally occurring mutants (P405R and P425L) of p73α and p73β found in neuroblastoma and lung cancer. Oncogene 20, 3568–3572 (2001). https://doi.org/10.1038/sj.onc.1204470
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DOI: https://doi.org/10.1038/sj.onc.1204470
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