The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor
FoxO transcription factors have a conserved role in longevity, and act as tissue-specific tumor suppressors in mammals. Several nodes of interaction have been identified between FoxO transcription factors and p53, a major tumor suppressor in humans and mice. However, the extent and importance of the...
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Published in | Oncogene Vol. 30; no. 29; pp. 3207 - 3221 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
21.07.2011
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | FoxO transcription factors have a conserved role in longevity, and act as tissue-specific tumor suppressors in mammals. Several nodes of interaction have been identified between FoxO transcription factors and p53, a major tumor suppressor in humans and mice. However, the extent and importance of the functional interaction between FoxO and p53 have not been fully explored. Here, we show that p53 regulates the expression of
FoxO3,
one of the four mammalian
FoxO
genes, in response to DNA damaging agents in both mouse embryonic fibroblasts and thymocytes. We find that p53 transactivates
FoxO3
in cells by binding to a site in the second intron of the
FoxO3
gene, a genomic region recently found to be associated with extreme longevity in humans. While FoxO3 is not necessary for p53-dependent cell cycle arrest, FoxO3 appears to modulate p53-dependent apoptosis. We also find that
FoxO3
loss does not interact with
p53
loss for tumor development
in vivo
, although the tumor spectrum of
p53
-deficient mice appears to be affected by
FoxO3
loss. Our findings indicate that
FoxO3
is a p53 target gene, and suggest that FoxO3 and p53 are part of a regulatory transcriptional network that may have an important role during aging and cancer. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 |
ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/onc.2011.35 |