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
TLDR
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.Abstract:
1 Laboratory For Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology (VIB), University of Ghent, Technologiepark, 927, Ghent B9052, Belgium 2 Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, CA 92037, USA 3 Gene Expression and Diseases Unit, Institut Pasteur, Paris, France 4 The University of Texas Graduate School of Biomedical Sciences and department of Molecular Genetics, Section of Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA * Corresponding author: J-C Marine, Laboratory For Molecular Cancer Biology, VIB, Technologiepark, 927, Ghent B-9052, Belgium. Tel: þ 32-93-313-640; Fax: þ 32-93-313-516; E-mail: chris.marine@dmbr.ugent.beread more
Citations
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Journal ArticleDOI
Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma.
Shatha AbuHammad,Carleen Cullinane,Carleen Cullinane,Claire Martin,Zoe Bacolas,Teresa Ward,Huiqin Chen,Alison Slater,Kerry Ardley,Laura Kirby,Keefe T. Chan,Keefe T. Chan,Natalie Brajanovski,Lorey K. Smith,Lorey K. Smith,Aparna D. Rao,Emily J. Lelliott,Emily J. Lelliott,Margarete Kleinschmidt,Ismael A. Vergara,Ismael A. Vergara,Anthony T. Papenfuss,Anthony T. Papenfuss,Anthony T. Papenfuss,Peter Lau,Peter Lau,Prerana Ghosh,Sue Haupt,Sue Haupt,Ygal Haupt,Ygal Haupt,Ygal Haupt,Elaine Sanij,Elaine Sanij,Gretchen Poortinga,Gretchen Poortinga,Richard B. Pearson,Richard B. Pearson,Richard B. Pearson,Hendrik Falk,David J. Curtis,Stupple Paul Anthony,Mark G. Devlin,Ian P. Street,Ian P. Street,Michael A. Davies,Grant A. McArthur,Grant A. McArthur,Karen E. Sheppard,Karen E. Sheppard +49 more
TL;DR: It is established that palbociclib inhibition of the PRMT5–MDM4 axis is essential for robust melanoma cell sensitivity and preclinical evidence that coinhibition of CDK4/6 andPRMT5 is an effective and well-tolerated therapeutic strategy is provided.
Journal ArticleDOI
The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity.
Vinod Pant,Shunbin Xiong,James G. Jackson,Sean M. Post,Hussein A. Abbas,Alfonso Quintás-Cardama,Amirali N. Hamir,Guillermina Lozano +7 more
TL;DR: While basal Mdm2 levels are sufficient to regulate p53 in most tissues under homeostatic conditions, the p53-Mdm2 feedback loop is critical for regulating p53 activity and sustaining HSC function after DNA damage, and transient disruption of p 53-MDM2 interaction could be explored as a potential adjuvant/therapeutic strategy for targeting stem cells in hematological malignancies.
Book ChapterDOI
p53-Independent Effects of Mdm2
TL;DR: Dysregulation of p53-independent functions could be responsible for the oncogenic properties of Mdm2 seen even in the absence of p 53, and may explain why approximately 10 % of human tumors overexpress MDM2 instead of inactivating p53 through other mechanisms.
Journal ArticleDOI
Distinct roles of Mdm2 and Mdm4 in red cell production
Marion M. Maetens,Marion M. Maetens,Gilles Doumont,Sarah De Clercq,Sarah Francoz,Sarah Francoz,Pascal Froment,Eric Bellefroid,Ursula Klingmüller,Guillermina Lozano,Jean-Christophe Marine +10 more
TL;DR: The data show that Mdm2 is required for rescuing erythroid progenitors from p53-mediated apoptosis during primitive erythropoiesis, and Mdm4 only contributes to p53 regulation at a specific phase of the differentiation program.
Journal ArticleDOI
Mitochondrial liaisons of p53.
Lorenzo Galluzzi,Eugenia Morselli,Eugenia Morselli,Eugenia Morselli,Oliver Kepp,Oliver Kepp,Oliver Kepp,Ilio Vitale,Ilio Vitale,Ilio Vitale,Marcello Pinti,Guido Kroemer +11 more
TL;DR: The tumor suppressor protein p53 is best known for its ability to orchestrate a transcriptional response to stress that can have multiple outcomes, including cell cycle arrest and cell death, but also involves transcription-independent mechanisms.
References
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Journal ArticleDOI
WAF1, a potential mediator of p53 tumor suppression
Wafik S. El-Deiry,Takashi Tokino,Victor E. Velculescu,Daniel B. Levy,Ramon Parsons,Jeffrey M. Trent,D Lin,W. Edward Mercer,Kenneth W. Kinzler,Bert Vogelstein +9 more
TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.
Journal ArticleDOI
In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
Lyubomir T. Vassilev,Binh Thanh Vu,Bradford Graves,Daisy Carvajal,Frank John Podlaski,Zoran Filipovic,Norman Kong,Ursula Kammlott,Christine Lukacs,Christian Klein,Nader Fotouhi,Liu Emily Aijun +11 more
TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.
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 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.
Journal ArticleDOI
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
TL;DR: The data suggest that the MDM2 protein, which is induced by p53, functions as a ubiquitin ligase, E3, in human papillomavirus‐uninfected cells which do not have E6 protein.