The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
MDM2 Acts Downstream of p53 as an E3 Ligase to Promote FOXO Ubiquitination and Degradation
Open accessAbstract
Members of the FOXO (forkhead O) class of transcription factors are tumor suppressors that also control aging and organismal life span. Mammalian FOXO degradation is proteasome-mediated, although the ubiquitin E3 ligase for FOXO factors remains to be defined. We show that MDM2 binds to FOXO1 and FOXO3A and promotes their ubiquitination and degradation, a process apparently dependent on FOXO phosphorylation at AKT sites and the E3 ligase activity of MDM2. Binding of MDM2 to FOXO occurs through the region of MDM2 that directs its cellular trafficking and the forkhead box of FOXO1. MDM2 promotes the ubiquitination of FOXO1 in a cell-free system, and its knockdown by small interfering RNA causes accumulation of endogenous FOXO3A protein in cells and enhances the expression of FOXO target genes. In cells stably expressing a temperature-sensitive p53 mutant, activation of p53 by shifting to permissive temperatures leads to MDM2 induction and degradation of endogenous FOXO3A. These data suggest that MDM2 acts as an ubiquitin E3 ligase, downstream of p53, to regulate the degradation of mammalian FOXO factors.
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Cites
Mdm2 promotes the rapid degradation of p53
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Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2
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Cited by
FOXOs: signalling integrators for homeostasis maintenance
Eijkelenboom, A., & Burgering, B. M. T. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3507 · Cited by 1,080
FoxO transcription factors; Regulation by AKT and 14-3-3 proteins
Tzivion, G., Dobson, M., & Ramakrishnan, G. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.06.002 · Cited by 728
Insulin/insulin-like growth factor signaling in C. elegans
Murphy, C. T. (2013) · WormBook · doi:10.1895/wormbook.1.164.1 · Cited by 532
Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System
Kocaturk, N. M., & Gozuacik, D. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00128 · Cited by 419
The MDM2-p53 pathway revisited
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Metadata
- Authors
- Fu, W., Ma, Q., Chen, L., Li, P., Zhang, M., Ramamoorthy, S., Nawaz, Z., Shimojima, T., Wang, H., Yang, Y., Shen, Z., Zhang, Y., Zhang, X., Nicosia, S. V., Zhang, Y., Pledger, J. W., Chen, J., & Bai, W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 284
- Issue
- 21
- Pages
- 13987-14000
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2047884499
- Cited by
- 201
- References
- 13
- FWCI
- 5.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- CoChat. (2026). Citation check: MDM2 Acts Downstream of p53 as an E3 Ligase to Promote FOXO Ubiquitination and Degradation. https://app.cochat.ai/papers/10.1074/jbc.m901758200
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- Fu, W., Ma, Q., Chen, L., Li, P., Zhang, M., Ramamoorthy, S., Nawaz, Z., Shimojima, T., Wang, H., Yang, Y., Shen, Z., Zhang, Y., Zhang, X., Nicosia, S. V., Zhang, Y., Pledger, J. W., Chen, J., & Bai, W. (2009). MDM2 Acts Downstream of p53 as an E3 Ligase to Promote FOXO Ubiquitination and Degradation. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m901758200
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