Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4.
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.
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
Citations
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TL;DR: Recent insights into MDM2 and MDM4 regulatory functions and their implications for the design of future p53-based anticancer strategies are highlighted.
232 citations
Cites background from "Keeping p53 in check: essential and..."
...The observation that MDM4-deficient embryos die around 10 dpc, apparently from p53-dependent cell proliferation arrest, showed that MDM4 is also an essential p53 regulator (Marine et al., 2006)....
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...…applies to many tissues, although it remains possible that the relative contribution of MDM2 and MDM4 to p53 regulation varies in some tissues or during specific differentiation phases (discussed in Boesten, Zadelaar, & De Clercq, 2006; Maetens, Doumont, & De Clercq, 2007; Marine et al., 2006)....
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...The notion that MDM2 is a major p53 regulator was confirmed in vivo when MDM2-deficient embryos were found to die around 4 days post-coitum (dpc) from p53dependent apoptosis (reviewed in Marine et al., 2006)....
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TL;DR: An organometallic glycogen synthase kinase 3beta (GSK3beta) inhibitor (DW1/2) is described as a potent activator of p53 and inducer of cell death in otherwise highly chemoresistant melanoma cells and may offer new hope for rational melanoma therapy.
Abstract: Unlike other tumors, melanomas harbor wild-type (WT) p53 but exhibit impaired p53-dependent apoptosis. The mechanisms for the impaired p53 activation are poorly understood but may be linked to the high expression of the p53 suppressor Mdm2, which is found in >50% of melanoma lesions. Here, we describe an organometallic glycogen synthase kinase 3beta (GSK3beta) inhibitor (DW1/2) as a potent activator of p53 and inducer of cell death in otherwise highly chemoresistant melanoma cells. Using RNA interference and pharmacologic approaches, we show that p53 is required for the cytotoxic effects of this organometallic inhibitor. The DW1/2 compound was barely able to induce cell death in melanoma cells with p53 mutations, further confirming the requirement for p53-WT in the cytotoxic effects of the GSK3beta inhibition. Mechanistic analysis of the p53-dependent cell death indicated an apoptotic mechanism involving depolarization of mitochondrial membrane potential, caspase cleavage, and elevated NOXA expression. The effect of p53 was not simply due to passive up-regulation of protein expression as adenoviral-mediated overexpression of p53 was not able to induce cell death. Treatment of melanoma cells with DW1/2 was instead found to decrease levels of Mdm2 and Mdm4. The importance of Mdm2 down-regulation in DW1/2-induced apoptosis was confirmed by treating the p53-WT cells with the p53/Mdm2 antagonist Nutlin-3. Taken together, our data provide a new strategy for the pharmacologic activation of p53 in melanoma, which may be a viable approach for overcoming apoptotic resistance in melanoma and offer new hope for rational melanoma therapy.
222 citations
TL;DR: In this paper, a review of shared interactors of p53-family proteins with the aim to encourage research into this field is presented. But the authors focus on the interactions between p53 and its p53 relatives, such as p73 and p63.
Abstract: The tumor suppressor p53 is a central hub in a molecular network controlling cell proliferation and death in response to potentially oncogenic conditions, and a wide array of covalent modifications and protein interactions modulate the nuclear and cytoplasmic activities of p53 The p53 relatives, p73 and p63, are entangled in the same regulatory network, being subject at least in part to the same modifications and interactions that convey signals on p53, and actively contributing to the resulting cellular output The emerging picture is that of an interconnected pathway, in which all p53-family proteins are involved in the response to oncogenic stress and physiological inputs Therefore, common and specific interactors of p53-family proteins can have a wide effect on function and dysfunction of this pathway Many years of research have uncovered an impressive number of p53-interacting proteins, but much less is known about protein interactions of p63 and p73 Yet, many interactors may be shared by multiple p53-family proteins, with similar or different effects In this study we review shared interactors of p53-family proteins with the aim to encourage research into this field; this knowledge promises to unveil regulatory elements that could be targeted by a new generation of molecules, and allow more efficient use of currently available drugs for cancer treatment
221 citations
Cites background from "Keeping p53 in check: essential and..."
...not induce p53 degradation directly, but can antagonize p53-dependent transcription.(35) However, MDMX and MDM2 heterodimerize to augment p53 degradation, and hence both proteins can potentially influence p53 stability....
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TL;DR: Understanding the molecular mechanisms that determine which response is selected may allow us to modulate these pathways so that therapeutic reactivation of p53 favours apoptotic cell death in tumour cells, but a reversible - and therefore far less toxic - induction of cell cycle arrest in normal cells.
Abstract: The p53 tumour suppressor protein can efficiently inhibit tumour development. This activity reflects its ability to induce a number of different responses, including cell cycle arrest and apoptosis. Recent studies have revealed some interesting insights into how the choice of response to p53 is regulated, highlighting a correlation between the activation of cell cycle arrest and survival with the ability of p53 to reduce oxidative stress and protect cells from genotoxic damage. Understanding the molecular mechanisms that determine which response is selected may allow us to modulate these pathways so that therapeutic reactivation of p53 favours apoptotic cell death in tumour cells, but a reversible--and therefore far less toxic--induction of cell cycle arrest in normal cells.
200 citations
Cites background from "Keeping p53 in check: essential and..."
...Clearly, activation of p53 in normal tissues following inducible loss of MDM2 can induce apoptosis in certain normal tissue types, which suggests that the tumour-to-normal-cell differential may not be as tight as one might have hoped (Marine et al., 2006)....
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TL;DR: Understanding the dysregulation of MDM2 and MDMX in human cancers and how they function either together or separately in tumorigenesis may improve methods of diagnosis and for assessing prognosis.
Abstract: For more than 25 years, MDM2 and its homolog MDMX (also known as MDM4) have been shown to exert oncogenic activity. These two proteins are best understood as negative regulators of the p53 tumor suppressor, although they may have additional p53-independent roles. Understanding the dysregulation of MDM2 and MDMX in human cancers and how they function either together or separately in tumorigenesis may improve methods of diagnosis and for assessing prognosis. Targeting the proteins themselves, or their regulators, may be a promising therapeutic approach to treating some forms of cancer.
199 citations
References
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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.
8,339 citations
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.
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.
4,397 citations
TL;DR: It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
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.
4,311 citations
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.
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.
3,298 citations
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.
1,962 citations