Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4.

doi:10.1038/SJ.CDD.4401912

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Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4.

Journal Article•DOI•

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4.

Jean-Christophe Marine¹, Sarah Francoz, Marion M. Maetens, Geoffrey M. Wahl², Franck Toledo², Franck Toledo³, Guillermina Lozano - Show less +3 more•Institutions (3)

Ghent University¹, Salk Institute for Biological Studies², Pasteur Institute³

01 Jun 2006-Cell Death & Differentiation (NATURE PUBLISHING GROUP)-Vol. 13, Iss: 6, pp 927-934

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.

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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.be

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Journal Article•DOI•

p53-Mediated Hematopoietic Stem and Progenitor Cell Competition

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Tanya Bondar¹, Ruslan Medzhitov¹•Institutions (1)

Yale University¹

02 Apr 2010-Cell Stem Cell

TL;DR: A form of cell competition that selects for the least damaged cells is described that is controlled by p53 but is distinct from the classical p53-mediated DNA damage response.

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294 citations

Cites background from "Keeping p53 in check: essential and..."

...1 were from Jackson Laboratory; Rosa26-eYFP mice were a kind gift of Dr. Frank Costantini; Hk-Bcl2 mice were a kind gift of Dr. Irving Weissman; Mdm2+/ mice were a kind gift of Dr. Jean-Christoph Marine. p53 / mice were crossed to CD45....
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...The activity of p53 is highly sensitive to the level of Mdm2 (Marine et al., 2006). mdm2+/ mice display enhanced p53 responses to stress but have normal hematopoiesis (Mendrysa et al., 2006)....
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...We thank Dr. Klaus Rajewsky for Rosa26 targeting vector and Bruce4 ESCs; Dr. Frank Costantini for providing Rosa26-LSL-eYFP mice; Dr. Irving Weissman for providing Hk-Bcl2 mice; Dr. Jean-Christophe Marine for providing Mdm2+/ mice; Timothy Nottoli for technical assistance in generating R26mp53 knockin mice; Charles Anicelli and Sophie Cronin for expert mouse work; Gouzel Tokmulina, Tom Taylor, and Xiao Xiao for FACS sorting; Bohwoo Kim and Sasha Stone for technical assistance; all R.M. lab members for insightful discussions; and Maya Kotas, Oscar Colegio, Arun Unni, and Dan Stetson for critical reading of the manuscript....
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...The activity of p53 is highly sensitive to the level of Mdm2 (Marine et al., 2006)....
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Journal Article•DOI•

A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression

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Nobuhiro Okada¹, Chao Po Lin¹, Marcelo C. Ribeiro¹, Anne Biton¹, Gregory Lai¹, Xingyue He², Pengcheng Bu¹, Hannes Vogel³, David M. Jablons⁴, Andreas Keller⁵, Andreas Keller⁶, J. Erby Wilkinson⁷, Biao He⁴, Terry P. Speed¹, Lin He¹ - Show less +11 more•Institutions (7)

University of California, Berkeley¹, Takeda Pharmaceutical Company², Stanford University³, University of California, San Francisco⁴, Siemens⁵, Saarland University⁶, University of Michigan⁷

01 Mar 2014-Genes & Development

TL;DR: The results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.

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Abstract: As bona fide p53 transcriptional targets, miR-34 microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect. However, miR-34a deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, suggesting that the defective p53-miR-34 feedback loop can enhance oncogenesis in a specific context. The importance of the p53/miR-34/HDM4 feedback loop is further confirmed by an inverse correlation between miR-34 and full-length HDM4 in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short HDM4 isoform through alternative polyadenylation. This short HDM4 isoform lacks miR-34-binding sites in the 3' untranslated region (UTR), thereby evading miR-34 regulation to disable the p53-miR-34 positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.

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251 citations

Cites background from "Keeping p53 in check: essential and..."

...…as one major negative regulator of p53 (Marine et al. 2006; Markey and Berberich 2008; Mandke et al. 2012; Wade et al. 2013). mdm4/HDM4 and its closely related homolog, mdm2/HDM2, both encode RING domain proteins that promote oncogenesis by inhibiting p53 (Marine et al. 2006; Wade et al. 2013)....
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...mdm4/HDM4 and its closely related homolog, mdm2/HDM2, both encode RING domain proteins that promote oncogenesis by inhibiting p53 (Marine et al. 2006; Wade et al. 2013)....
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...S2H) and its important functions as one major negative regulator of p53 (Marine et al. 2006; Markey and Berberich 2008; Mandke et al. 2012; Wade et al. 2013)....
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...S2H) and its important functions as one major negative regulator of p53 (Marine et al. 2006; Markey and Berberich 2008; Mandke et al. 2012; Wade et al. 2013). mdm4/HDM4 and its closely related homolog, mdm2/HDM2, both encode RING domain proteins that promote oncogenesis by inhibiting p53 (Marine et…...
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Journal Article•DOI•

Cellular stress response pathway system as a sentinel ensemble in toxicological screening

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Steven O. Simmons¹, Chun-Yang Fan¹, Chun-Yang Fan², Ram Ramabhadran¹•Institutions (2)

Research Triangle Park¹, University of North Carolina at Chapel Hill²

01 Oct 2009-Toxicological Sciences

TL;DR: The biochemical characteristics of the stress response pathways, their common architecture that enables rapid activation during stress, their participation in cell fate decisions, the essential nature of these pathways to the organism, and the biochemical basis of their cross-talk that permits an assay ensemble screening approach are reviewed.

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246 citations

Cites background from "Keeping p53 in check: essential and..."

...Disruption of Mdm2 (Marine et al., 2006), KEAP1 (Wakabayashi et al., 2003), NFKBIA (IjB; (Gerondakis et al., 2006), VHL (Kapitsinou and Haase, 2008), which respectively regulate p53, Nrf2, NF-jB, and HIF-1a all result in embryonic or postnatal lethal phenotypes....
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...Lastly, p53 stimulates the expression of its sensor Mdm2, providing a negative feedback loop to surviving cells; however, Mdm2 is considered a late response target, which provides a temporal window for active p53 to affect cell cycle, DNA repair, and/or apoptosis (Lahav et al., 2004)....
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...Under normal conditions, p53 is constitutively expressed, but is negatively regulated by the pathway sensor, Mdm2....
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...Interestingly however, where data are available, the simultaneous genetic deletion of both the sensor and corresponding TF genes rescues the embryonic lethal phenotype that results from deleting the sensor gene alone as evidenced by the viability of double knockout mice such as p53-Mdm2 (Jones et al., 1995; Marine et al., 2006) and Nrf2-Keap1 (Motohashi and Yamamoto, 2004)....
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...In addition to physically sequestering p53 in the cytoplasm, Mdm2 also directs p53 to ubiquitinmediated proteasomal degradation, thus reducing p53 protein half-life to mere minutes....
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Journal Article•DOI•

Mdm2 Regulates p53 mRNA Translation through Inhibitory Interactions with Ribosomal Protein L26

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Yaara Ofir-Rosenfeld¹, Kristy Boggs², Dan Michael¹, Michael B. Kastan², Moshe Oren¹ - Show less +1 more•Institutions (2)

Weizmann Institute of Science¹, St. Jude Children's Research Hospital²

24 Oct 2008-Molecular Cell

TL;DR: It is reported that Mdm2 regulates p53 levels also by targeting ribosomal protein L26, which represents an additional important component of the autoregulatory feedback loop that dictates cellular p53 Levels and activity.

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242 citations

Cites background from "Keeping p53 in check: essential and..."

...…enhanced Mdm2 degradation, posttranslational modifications on p53 and Mdm2, altered binding to other proteins that modulate the p53-Mdm2 interaction and its consequences, and altered subcellular localization of p53 and Mdm2 (reviewed in Marine et al., 2006; Oren, 2003; Toledo and Wahl, 2006)....
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...The p53 tumor suppressor protein is a pivotal regulator of cell fate, particularly under conditions of stress (Aylon and Oren, 2007; Harris and Levine, 2005; Marine et al., 2006; Poyurovsky and Prives, 2006; Riley et al., 2008). p53 is subject to exquisite regulation....
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...The p53 tumor suppressor protein is a pivotal regulator of cell fate, particularly under conditions of stress (Aylon and Oren, 2007; Harris and Levine, 2005; Marine et al., 2006; Poyurovsky and Prives, 2006; Riley et al., 2008)....
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...One key regulator of p53 is the mouse double minute 2 (Mdm2) protein, which binds specifically to p53 and inhibits many of p53’s biochemical activities (Marine et al., 2006; Michael and Oren, 2003)....
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Journal Article•DOI•

MDMX: from bench to bedside.

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Jean-Christophe Marine¹, Michael A. Dyer², Aart G. Jochemsen³•Institutions (3)

Ghent University¹, St. Jude Children's Research Hospital², Leiden University Medical Center³

01 Feb 2007-Journal of Cell Science

TL;DR: Specific MDMX antagonists should be developed as a tool to ensure activation of `dormant' p53 activity in tumors that retain wild-type p53.

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Abstract: The tumor suppressor protein p53 is negatively regulated by Mdm2, a ubiquitin ligase protein that targets p53 for degradation. Mdmx (also known as Mdm4) is a relative of Mdm2 that was identified on the basis of its ability to physically interact with p53. An increasing body of evidence, including recent genetic studies, suggests that Mdmx also acts as a key negative regulator of p53. Aberrant expression of MDMX could thus contribute to tumor formation. Indeed, MDMX amplification and/or overexpression occurs in several diverse tumors. Strikingly, recent work identifies MDMX as a specific chemotherapeutic target for treatment of retinoblastoma. Specific MDMX antagonists should therefore be developed as a tool to ensure activation of 'dormant' p53 activity in tumors that retain wild-type p53.

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236 citations

Cites background from "Keeping p53 in check: essential and..."

...There is now clear genetic evidence indicating that Mdmx contributes to the regulation of p53 independently of Mdm2 and that both proteins act synergistically to keep p53 in check (Francoz et al., 2006; Marine et al., 2006)....
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...Recent studies show that Mdm2 is required to maintain p53 at low levels both in proliferating and in post-mitotic cells (reviewed by Marine et al., 2006)....
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...Recent genetic studies are not entirely consistent with a role for Mdm2 in the regulation of p53 transcriptional activity per se, however (Marine et al., 2006)....
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References

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Journal Article•DOI•

WAF1, a potential mediator of p53 tumor suppression

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Wafik S. El-Deiry¹, Takashi Tokino¹, Victor E. Velculescu¹, Daniel B. Levy¹, Ramon Parsons¹, Jeffrey M. Trent, D Lin², W. Edward Mercer², Kenneth W. Kinzler¹, Bert Vogelstein¹ - Show less +6 more•Institutions (2)

Johns Hopkins University School of Medicine¹, Thomas Jefferson University²

19 Nov 1993-Cell

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.

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8,339 citations

Journal Article•DOI•

In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.

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Lyubomir T. Vassilev¹, Binh Thanh Vu¹, Bradford Graves¹, Daisy Carvajal¹, Frank John Podlaski¹, Zoran Filipovic¹, Norman Kong¹, Ursula Kammlott¹, Christine Lukacs¹, Christian Klein¹, Nader Fotouhi¹, Liu Emily Aijun¹ - Show less +8 more•Institutions (1)

Hoffmann-La Roche¹

06 Feb 2004-Science

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.

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Abstract: MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.

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4,397 citations

Journal Article•DOI•

Mdm2 promotes the rapid degradation of p53

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Ygal Haupt¹, Ruth Maya², Anat Kazaz², Moshe Oren²•Institutions (2)

Hebrew University of Jerusalem¹, Weizmann Institute of Science²

15 May 1997-Nature

TL;DR: It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.

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Abstract: The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.

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4,311 citations

Journal Article•DOI•

Regulation of p53 stability by Mdm2

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Michael H. G. Kubbutat, Stephen N. Jones¹, Karen H. Vousden•Institutions (1)

Baylor College of Medicine¹

15 May 1997-Nature

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.

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Abstract: The tumour-suppressor p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Stabilization of the protein in response to an activating signal, such as DNA damage, results in a rapid rise in p53 levels and subsequent inhibition of cell growth. Tight regulation of p53 function is critical for normal cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein. Mdm2 inhibits p53 cell-cycle arrest and apoptic functions and we show here that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation. Endogenous levels of Mdm2 are sufficient to regulate p53 stability, and overexpression of Mdm2 can reduce the amount of endogenous p53. Because mdm2 is transcriptionally activated by p53, this degradative pathway may contribute to the maintenance of low p53 concentrations in normal cells. Furthermore, mechanisms regulating the Mdm2-induced degradation of p53 may play a role in controlling the extent and duration of the p53 response.

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3,298 citations

Journal Article•DOI•

Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53

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Reiko Honda¹, Hirofumi Tanaka¹, Hideyo Yasuda¹•Institutions (1)

University of Tokyo¹

22 Dec 1997-FEBS Letters

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.

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1,962 citations