Regulation of MDM4 (MDMX) function by p76 MDM2 : a new facet in the control of p53 activity
Simona Giglio,Francesca Mancini,Marsha Pellegrino,G Di Conza,Efisio Puxeddu,Ada Sacchi,Alfredo Pontecorvi,Fabiola Moretti +7 more
TLDR
A new mechanism in the control of p53 basal activity is revealed that may account for the distinct sensitivity of tissues to stress signals depending on the balance among MDM proteins.Abstract:
Under basal growth conditions, p53 function is tightly controlled by the members of MDM family, MDM2 and MDM4. The Mdm2 gene codes, in addition to the full-length p90(MDM2), for a short protein, p76(MDM2) that lacks the p53-binding domain. Despite this property and at variance with p90(MDM2), this protein acts positively toward p53, although the molecular mechanism remains elusive. Here, we report that p76(MDM2) antagonizes MDM4 inhibitory function. We show that p76(MDM2) possesses intrinsic ubiquitinating and degrading activity, and through these activities controls MDM4 levels. Furthermore, the presence of p76(MDM2) decreases the association of MDM4 with p53 and p90(MDM2), and antagonizes p53 degradation by the heterodimer MDM4/p90(MDM2). The p76(MDM2)-mediated regulation of MDM4 occurs in the cytoplasm, under basal growth conditions. Conversely, upon DNA damage, phosphorylation of MDM4Ser403 dissociates p76(MDM2) and prevents MDM4 degradation. The overall negative control of MDM4 by p76(MDM2) reflects on p53 function as p76(MDM2) impairs MDM4-mediated inhibition of p53 activity. In agreement with the positive role of p76(MDM2) toward p53, the p76(MDM2)/p90(MDM2) ratio significantly decreases in a group of thyroid tumor samples compared with normal counterparts. Overall, these findings reveal a new mechanism in the control of p53 basal activity that may account for the distinct sensitivity of tissues to stress signals depending on the balance among MDM proteins. Moreover, these data suggest an oncosuppressive function for a product of the Mdm2 gene.read more
Citations
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Phospho-ΔNp63α/miR-885-3p axis in tumor cell life and cell death upon cisplatin exposure
TL;DR: The results support the notion that miR-885-3p might contribute in regulation of cell viability, apoptosis and/or autophagy in squamous cell carcinoma cells upon cisplatin exposure.
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Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy.
Meaghan Van Alstyne,Christian M. Simon,S. Pablo Sardi,Lamya S. Shihabuddin,George Z. Mentis,Livio Pellizzoni +5 more
TL;DR: It is revealed that loss of SMN-dependent regulation of Mdm2 and Mdm4 alternative splicing underlies p53-mediated death of motor neurons in SMA, establishing a causal link between snRNP dysfunction and neurodegeneration.
Journal ArticleDOI
Zmat3 Is a Key Splicing Regulator in the p53 Tumor Suppression Program
Kathryn T. Bieging-Rolett,Alyssa M. Kaiser,David W. Morgens,Anthony M. Boutelle,Jose A. Seoane,Eric L. Van Nostrand,Changyu Zhu,Shauna L. Houlihan,Stephano S. Mello,Brian A. Yee,Jacob McClendon,Sarah E. Pierce,Ian P. Winters,Mengxiong Wang,Andrew J. Connolly,Scott W. Lowe,Christina Curtis,Gene W. Yeo,Monte M. Winslow,Michael C. Bassik,Laura D. Attardi +20 more
TL;DR: Unbiased RNAi and CRISPR-Cas9-based genetic screens in vivo reveal ZMAT3 as a novel RNA-splicing and homeostasis regulator and a key component of p53-mediated tumor suppression.
Journal ArticleDOI
MDM4/HIPK2/p53 cytoplasmic assembly uncovers coordinated repression of molecules with anti-apoptotic activity during early DNA damage response.
Francesca Mancini,Francesca Mancini,Luisa Pieroni,Valentina Monteleone,Rossella Lucà,Laura Fici,Laura Fici,Emilia Luca,Emilia Luca,Andrea Urbani,S. Xiong,Silvia Soddu,Riccardo Masetti,G. Lozano,Alfredo Pontecorvi,Fabiola Moretti +15 more
TL;DR: Flexibility of MDM2/MDM4 heterodimer allows the development of a positive activity of cytoplasmic MDM4 towards p53-mediated transcriptional function, which uncovers coordinated repression of molecules with shared anti-apoptotic function which precedes active cell apoptosis.
Journal ArticleDOI
Mutation in Eftud2 causes craniofacial defects in mice via mis-splicing of Mdm2 and increased P53.
Marie-Claude Beauchamp,Anissa Djedid,Eric Bareke,Fjodor Merkuri,Rachel Aber,Annie S. Tam,Annie S. Tam,Matthew A. Lines,Kym M. Boycott,Peter C. Stirling,Peter C. Stirling,Jennifer L. Fish,Jacek Majewski,Loydie A. Jerome-Majewska +13 more
TL;DR: In this paper, a mutant mouse line with conditional mutation in Eftud2 and used Wnt1-Cre2 to delete it in neural crest cells was generated and RNAseq analysis of embryonic heads revealed a significant increase in exon skipping and increased levels of an alternatively spliced Mdm2 transcript lacking exon 3.
References
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Journal ArticleDOI
MDMX: A novel p53-binding protein with some functional properties of MDM2
A. Shvarts,W. T. Steegenga,N. Riteco,T. van Laar,P. Dekker,M. Bazuine,R. C. A. Van Ham,W. van der Houven van Oordt,G. Hateboer,A. J. Van Der Eb,Aart G. Jochemsen +10 more
TL;DR: The isolation of a cDNA encoding a new p53‐associating protein, called MDMX, is reported, which indicates that at least one additional member of the MDM protein family exists which can modulate p53 function.
Journal ArticleDOI
HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53.
TL;DR: Surprisingly, data indicate that HdmX acts as a stimulator, rather than as an inhibitor, of the E3 activity of Hdm2 and that, at least under certain conditions, HDMX is actively involved in the degradation of both p53 and HDM2.
Journal ArticleDOI
Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4.
Jean-Christophe Marine,Sarah Francoz,Marion M. Maetens,Geoffrey M. Wahl,Franck Toledo,Franck Toledo,Guillermina Lozano +6 more
TL;DR: This work presents a novel and scalable approach to gene expression engineering that allows for real-time annotation of gene expression changes in response to cancerigenicity and shows promise in finding novel and efficient treatments for cancer.
Journal ArticleDOI
Mdm2-mediated ubiquitylation: p53 and beyond
TL;DR: Advances in Mdm2-mediated regulation of p53 and how the physical and functional interactions between these two proteins are regulated are evaluated and their potential implications for the development of new cancer therapeutic strategies are reviewed.
Journal ArticleDOI
Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2
Erik Meulmeester,Madelon M. Maurice,Chris Boutell,Amina F A S Teunisse,Huib Ovaa,Tsion E. Abraham,Roeland W. Dirks,Aart G. Jochemsen +7 more
TL;DR: It is shown that HAUSP also interacts with Hdmx, resulting in its direct deubiquitination and stabilization, which contributes to the DNA damage-induced degradation of HDMx and transient instability of Hdm2.