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
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TL;DR: An increasing body of evidence now convincingly demonstrates a cross-talk between vitamin D- and p53-signaling that occurs at different levels, has genome-wide implications and that should be of high importance for many malignancies, including non-melanoma skin cancer.
Abstract: P53 and its family members have been implicated in the direct regulation of the vitamin D receptor (VDR). Vitamin D- and p53-signaling pathways have a significant impact on spontaneous or carcinogen-induced malignant transformation of cells, with VDR and p53 representing important tumor suppressors. VDR and the p53/p63/p73 proteins all function typically as receptors or sensors that turn into transcriptional regulators upon stimulus, with the main difference being that the nuclear VDR is activated as a transcription factor after binding its naturally occurring ligand 1,25-dihydroxyvitamin D with high affinity while the p53 family of transcription factors, mostly in the nucleoplasm, responds to a large number of alterations in cell homeostasis commonly referred to as stress. An increasing body of evidence now convincingly demonstrates a cross-talk between vitamin D- and p53-signaling that occurs at different levels, has genome-wide implications and that should be of high importance for many malignancies, including non-melanoma skin cancer. One interaction involves the ability of p53 to increase skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Pigmentation protects the skin against UV-induced DNA damage and skin carcinogenesis, yet on the other hand reduces cutaneous synthesis of vitamin D. A second level of interaction may be through the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression, and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute 2 (MDM2) gene in dependence of the presence of wild-type p53. MDM2 has a well-established role as a key negative regulator of p53 activity. Finally, p53 and family members have been implicated in the direct regulation of VDR. This overview summarizes some of the implications of the cross-talk between vitamin D- and p53-signaling for carcinogenesis in the skin and other tissues.
46 citations
TL;DR: The development of a cell-based assay used with a library of human miRNA mimics in a high-throughput screen for miRNAs that modulate p53 expression defines miR-542-3p as an important new positive regulator of p53 with potential applications in cancer treatment.
Abstract: The tumor suppressor p53 and microRNAs (miRNAs) are linked through a complex network. Several miRNAs modulate p53 expression, while p53 regulates the transcription and/or biogenesis of several other miRNAs. Here we report the development of a cell-based assay used with a library of human miRNA mimics in a high-throughput screen for miRNAs that modulate p53 expression. Overexpression of miR-542-3p in cancer cells elevated p53 expression, stimulated the expression of p53 targets and inhibited cell proliferation. Mechanistically, miR-542-3p increased p53 protein stability by weakening interactions between p53 and its negative regulator MDM2. Further, miR-542-3p suppressed ribosome biogenesis by downregulating a subset of ribosomal proteins such as RPS23, leading to upregulation of RPL11 and stabilization of p53. The 3'UTR in the RPS23 transcript contained a miR-542-3p binding site, suggesting that RPS23 is a direct target of miR-542-3p. Our results define miR-542-3p as an important new positive regulator of p53 with potential applications in cancer treatment.
46 citations
Cites background from "Keeping p53 in check: essential and..."
...S4), two known positive regulators of p53–MDM2 interaction (4, 28)....
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TL;DR: It is observed that a fraction of MDM4 stably localizes at the mitochondria where upon lethal stress conditions, promotes the mitochondrial localization of p53 phosphorylated at Ser46 (p53Ser46P) and facilitates its binding to BCL2, cytochrome C release and apoptosis.
Abstract: p53 is a crucial regulator of cell response to DNA damage. MDM4 and MDM2 are the two main negative regulators of p53 activity. Upon DNA damage, their constraint is released and p53 becomes activated and exerts its safeguard function by arresting cell growth or by killing excessively damaged cells. Under these conditions, increasing data suggest that MDM4 and MDM2 play novel roles. In this respect, we recently published that MDM4 exerts a positive activity towards p53 mitochondrial apoptosis. We observed that a fraction of MDM4 stably localizes at the mitochondria where upon lethal stress conditions, promotes the mitochondrial localization of p53 phosphorylated at Ser46 (p53Ser46(P)) and facilitates its binding to BCL2, cytochrome C release and apoptosis. Most importantly, we observed a correlation of MDM4 expression with cisplatin-resistance in a group of human ovarian cancers suggesting that MDM4 proapoptotic activity may have in vivo relevance. Here, we discuss about these and some new findings and compare them with previous data trying to settle some apparent contradictions. In addition, this review discusses the potential relevance of our data to the field of human cancer.
45 citations
Cites background from "Keeping p53 in check: essential and..."
...Although downregulation of MDM4 levels in human tumors has also been reported,(66-68) different factors may concur to explain this discrepancy: (1) MDM4 function may be tissue specific, particularly in the light of the different sensitivity of various organs to mitochondrial apoptosis....
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...Both of the fulllength proteins are crucial inhibitors of the tumor suppressor p53, a function that, per se, attributes oncogenic properties to them.(1,2) Their knock-out(KO) mice show embryonic lethality but have a normal development when simultaneously deleted for Trp53 gene, confirming their requirement for proper p53 regulation during mouse embryo development....
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TL;DR: Understanding the emerging field of how the UPS regulates HSC activity may lead to novel targets for therapy of leukemia.
45 citations
TL;DR: This comprehensive analysis of the Pirh2 and Mdm2 RING domains provides structural and mechanistic insight into p53 regulation by its E3 ligases.
44 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