ArticleJournal of molecular biology2008
Intrinsically unstructured domains of Arf and Hdm2 form bimolecular oligomeric structures in vitro and in vivo.
Article in Journal of molecular biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 37 citations in OpenAlex.
- Opportunities in cancer gene therapy: inhibiting MDM2 and restoring p14ARF as a means to activate p53.Molecular and cellular biochemistry · 2026Review
- ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss.Molecular cell · 2024Article
- p14Nature communications · 2024Article
- p14Research square · 2023Article
- Diversity of hydrodynamic radii of intrinsically disordered proteins.European biophysics journal : EBJ · 2023Article
- Bivalent binding of p14ARF to MDM2 RING and acidic domains inhibits E3 ligase function.Life science alliance · 2022Article
- Direct detection of carbon and nitrogen nuclei for high-resolution analysis of intrinsically disordered proteins using NMR spectroscopy.Methods (San Diego, Calif.) · 2018Article
- On the relationship status for Arf and NPM1 - it's complicated.The FEBS journal · 2018Article
- The evolution of Sex-linked barring alleles in chickens involves both regulatory and coding changes in CDKN2A.PLoS genetics · 2017Article
- Intrinsic α helix propensities compact hydrodynamic radii in intrinsically disordered proteins.Proteins · 2017Article
- Intra molecular interactions in the regulation of p53 pathway.Translational cancer research · 2016Article
- Dynamic Protein Interaction Networks and New Structural Paradigms in Signaling.Chemical reviews · 2016Review
- Hydrodynamic Radii of Intrinsically Disordered Proteins Determined from Experimental Polyproline II Propensities.PLoS computational biology · 2016Article
- Alanine and proline content modulate global sensitivity to discrete perturbations in disordered proteins.Proteins · 2014Article
- Autoactivation of the MDM2 E3 ligase by intramolecular interaction.Molecular and cellular biology · 2014Article
- Structural polymorphism in the N-terminal oligomerization domain of NPM1.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Ca2+-induced PRE-NMR changes in the troponin complex reveal the possessive nature of the cardiac isoform for its regulatory switch.PloS one · 2014Article
- Targeting p53-MDM2-MDMX loop for cancer therapy.Sub-cellular biochemistry · 2014Review
- The N-terminal basolateral targeting signal unlikely acts alone in the differential trafficking of membrane transporters in MDCK cells.Biochemistry · 2013Article
- The quiet renaissance of protein nuclear magnetic resonance.Biochemistry · 2013Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Arf, Hdm2, and p53 regulate the tumor-suppressor pathway that is most frequently disrupted in human cancer. In the absence of tumorigenic stress, Hdm2 actively attenuates p53-dependent cell cycle arrest and apoptosis by mediating ubiquitination-dependent degradation of p53. Mitogenic stress activates Arf, which indirectly activates p53 by binding to and nullifying the anti-p53 activities of Hdm2. Small conserved domains within Arf and Hdm2 mediate their direct interaction. Individually, these domains are intrinsically unstructured and, when combined in vitro, cofold into bimolecular oligomeric structures that resemble amyloid fibrils in some features. Detailed structural characterization of Hdm2/Arf complexes has previously been hampered by their heterogeneity and large size. Here, we report that a nine-residue fragment of the N-terminus of mouse Arf (termed "A1-mini") cofolds specifically with the Arf-binding domain of Hdm2 to form bimolecular oligomers. We characterized these unprecedented structures using analytical ultracentrifugation and NMR spectroscopy, providing insights into their structural organization. The A1-mini peptide not only binds specifically to Hdm2 in vitro but also recapitulates the nucleolar localization features of full-length Arf in cells. Furthermore, larger fragments of Arf that contain the A1-mini segment have previously been shown to activate p53 in mouse and human cells. Our studies provide the first insights into the molecular basis through which Arf nullifies the p53-inhibiting activity of Hdm2, indirectly activating the tumor-suppressor function of p53 in mammalian cells.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.