A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking.
Jayne M. Stommel,Natalie D. Marchenko,Gretchen S. Jimenez,Ute M. Moll,Thomas J. Hope,Geoffrey M. Wahl +5 more
Reads0
Chats0
TLDR
A model in which regulated p53 tetramerization occludes its NES is proposed, thereby ensuring nuclear retention of the DNA‐binding form and suggesting that attenuation of p53 function involves the conversion of tetramers into monomers or dimers, in which the NES is exposed to the proteins which mediate their export to the cytoplasm.Abstract:
Appropriate subcellular localization is crucial for regulating p53 function. We show that p53 export is mediated by a highly conserved leucine-rich nuclear export signal (NES) located in its tetramerization domain. Mutation of NES residues prevented p53 export and hampered tetramer formation. Although the p53-binding protein MDM2 has an NES and has been proposed to mediate p53 export, we show that the intrinsic p53 NES is both necessary and sufficient for export. This report also demonstrates that the cytoplasmic localization of p53 in neuroblastoma cells is due to its hyperactive nuclear export: p53 in these cells can be trapped in the nucleus by the export-inhibiting drug leptomycin B or by binding a p53-tetramerization domain peptide that masks the NES. We propose a model in which regulated p53 tetramerization occludes its NES, thereby ensuring nuclear retention of the DNA-binding form. We suggest that attenuation of p53 function involves the conversion of tetramers into monomers or dimers, in which the NES is exposed to the proteins which mediate their export to the cytoplasm.read more
Citations
More filters
Journal ArticleDOI
Transport between the cell nucleus and the cytoplasm.
Dirk Görlich,Ulrike Kutay +1 more
TL;DR: A focus of this review is nuclear export of messenger RNA, which apparently largely relies on export mediators distinct from importin beta-related factors.
Journal ArticleDOI
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Franck Toledo,Geoffrey M. Wahl +1 more
TL;DR: This Review of in vitro studies, human tumour data and recent mouse models shows that p53 post-translational modifications have modulatory roles, and MDM2 andMDM4 have more profound roles for regulating p53.
Journal ArticleDOI
Post-translational modification of p53 in tumorigenesis
Ann M. Bode,Zigang Dong +1 more
TL;DR: A thorough understanding of p53 will be extremely useful in the development of new strategies for treating and preventing cancer, including restoration of p 53 function and selective killing of tumours with mutant TP53.
Journal ArticleDOI
Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling
TL;DR: This work proposes a model where p53 can contribute to apoptosis by direct signaling at the mitochondria, thereby amplifying the transcription-dependent apoptosis of p53.
Journal Article
The MDM2-p53 Interaction
Ute M. Moll,Oleksi Petrenko +1 more
TL;DR: Because the p53-MDM2 interaction is structurally and biologically well understood, the design of small lipophilic molecules that disrupt or prevent it has become an important target for cancer therapy.
References
More filters
Journal ArticleDOI
MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures
TL;DR: The MOLSCRIPT program as discussed by the authors produces plots of protein structures using several different kinds of representations, including simple wire models, ball-and-stick models, CPK models and text labels.
Journal ArticleDOI
p53, the Cellular Gatekeeper for Growth and Division
TL;DR: The author regrets the lack of citations for many important observations mentioned in the text, but their omission is made necessary by restrictions in the preparation of review manuscripts.
Journal ArticleDOI
Mdm2 promotes the rapid degradation of p53
TL;DR: It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
Journal Article
Participation of p53 Protein in the Cellular Response to DNA Damage
TL;DR: A role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage is suggested and a new mechanism for how the loss of wild- type p53 might contribute to tumorigenesis is suggested.
Journal ArticleDOI
Regulation of p53 stability by Mdm2
TL;DR: It is shown that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation, which may contribute to the maintenance of low p53 concentrations in normal cells.