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Journal ArticleDOI

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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Dissertation
01 Jan 2011
TL;DR: The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders and female gender appears to be a strong predictor of a favourable outcome.
Abstract: From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume <190 ml, 24-h serum methotrexate >4.5 mM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in >70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome. # 2003 Elsevier Science Ltd. All rights reserved.

2 citations

Journal ArticleDOI
TL;DR: It is suggested that the MDM2 309G allele is significantly associated with prostate cancer risk, and should be functionally evaluated in vitro or through knockout or transgene techniques in animals to assess the potential for prostate cancer gene therapy.
Abstract: Murine double minute 2 (MDM2) is thought to be a critical negative regulator of p53. It has been suggested that overexpression of MDM2 could lead to inactivation of p53, which might play a vital role in carcinogenesis. It was observed in the study by Leite et al. that overexpression of MDM2 has a role in prostate carcinogenesis, being frequently detected and associated with increased cell proliferation and tumor volume. A single nucleotide polymorphism (SNP) in the MDM2 promoter, SNP309 T>G, has been identified, which might alter MDM2 expression and lead to tumor transformation. In this meta-analysis by Liu et al., the association of MDM2 SNP309 T>G polymorphism with prostate cancer risk was evaluated. Liu et al. found a significant association between MDM2 SNP309 polymorphism and prostate cancer risk. In subgroup analyses, a significant association was also detected in Caucasians. Liu et al. concluded that the MDM2 309G allele might act as a reduced risk factor for prostate cancer. The findings in the meta-analysis were interesting. However, some issues should be addressed regarding the meta-analysis. First, in order to provide a more precise estimation on the basis of adjustment for confounders, well-designed studies are warranted by taking potential confounders into account, such as age and smoking. Further studies are required to investigate the effects of the MDM2 309G allele on familial and sporadic prostate cancer, respectively. Second, quality assessment scores in the meta-analysis were assessed for included studies. According to the more convincing guide in the Cochrane Handbook, the use of scales for assessing quality is explicitly discouraged. Hence, the quality assessment scores for studies included in the meta-analysis should be used cautiously. Third , the MDM2 SNP309 polymorphism should be functionally evaluated in vitro or through knockout or transgene techniques in animals to assess the potential for prostate cancer gene therapy. Collectively, it suggests that the MDM2 309G allele is significantly associated with prostate cancer risk. Further study based on larger sample size is still required, especially in Asians and Africans. If the authors could take into account the aforementioned issues, a more accurate elaboration of the results would be provided.

2 citations

Dissertation
22 Sep 2014
TL;DR: This project investigated weather acidic TADs had the ability to function as UBDs and form non-covalent interactions with ubiquitin and also to determine the functional significance of this interaction in regards to the dual function of acidic T ADs.
Abstract: Acidic transactivating domains have been shown to be potential targets for a number of different therapies but their dynamic nature and their ability to bind many interacting partners has made it difficult to fully understand their functioning mechanisms. What we do know about these domains is that they readily control transcription through a myriad of interactions capable of either activating specific aspects of their function or simply, signal for their own demise. Within the acidic TADs lies an unusual degradation/activation domain (DAD) capable of activating transcription at the cost of its degradation. In other words, DAD transcriptional activation is dependent on the degradation of the protein. Such a phenomenon could be explained by a wide variety of hypotheses like the play of post-translational modifications, co-factors, or maybe just a really sophisticated time scaled network of interactions. However, no concrete explanation of how this dual dependent functioning domain works has yet to surface. The DAD has been observed within acidic TADs of several transcription factors including the tumor suppressor p53 and the red blood cell differentiation factor EKLF. Interestingly though, the amino acid sequence composition of DADs share a strong similarity with several types of sequences from domains that bind ubiquitin (UBDs). These domains have been shown in the past to, in addition to their role in degradation, play a key role in regulating transcription through non-covalent interaction with ubiquitin. Hence, in this project, we investigated weather acidic TADs had the ability to function as UBDs and form non-covalent interactions with ubiquitin and also to determine the functional significance of this interaction in regards to the dual function of acidic TADs.

2 citations


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

  • ...p53 sont modifiés post-traductionellement par une phosphorylation suite à un stimuli; (2) lorsque MDM2 est séquestré par l'induction oncogénique de la protéine de suppression de tumeurs p14ARF ou (3) lorsque MDM2 interagit avec des protéines ribosomales induites par des stress nucléolaires [44-46]....

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29 May 2013
TL;DR: In conclusion, therapeutic MDM2 blockade may hold the risk of impaired epithelial healing in AKI and could be a novel therapeutic strategy to prevent renal inflammation, podocyte loss, glomerulosclerosis, proteinuria, and progressive kidney disease.
Abstract: Murine double minute (MDM)-2, an E3 ubiquitin ligase, promotes cancer cell survival and growth, by degrading the cell cycle regulator p53. Antagonism of MDM2 by the small-molecule cis-imidazoline nutlin analogs is currently under study for cancer therapy. We observed that MDM2 is strongly expressed by the epithelial cells in the kidney for example, tubular epithelial cells and podocytes. To test whether MDM2 promotes regenerative cell growth, we studied the effects of MDM2 antagonist, nutlin-3a on tubule cell healing during postischemic acute kidney injury and on podocytes during adriamycin induced chronic renal failure. Consistent with the hypothesis, we observed that treatment with nutlin-3a impaired tubular cell regeneration during postischemic AKI in C57Bl6 wild-type mice in a p53-dependent manner. However, MDM2 blockade also prevented tubular necrosis by suppressing sterile inflammation during the early postischemic phase. This effect also occurred in p53-deficient mice, indicating a second, pro-inflammatory, p53-independent role for MDM2 in AKI. In-vitro experiments confirmed that MDM2 is required to induce mRNA expression and secretion of NF-κB-dependent cytokines upon Toll-like receptor stimulation by enhanced binding of NF-κB to cytokine promoter–binding sites. Thus, MDM2 links inflammation and epithelial healing during AKI. It promotes the inflammatory response after the injury at the same time it drives the regeneration of injured tubular epithelium. Therefore, these additional biological functions need to be regarded when considering MDM2 inhibition therapy in patients with acute renal failure. Since, podocytes strongly express MDM2, we hypothesized that blocking MDM2 during glomerular injury may enhance podocyte apoptosis, proteinuria and glomerulosclerosis. However, unexpectedly MDM2 blockade in early adriamycin nephropathy in Balb/c mice had the opposite effect and reduced intrarenal cytokine and chemokine expression, glomerular macrophage and T cell counts, plasma creatinine and BUN levels. In cultured podocytes exposed to adriamycin, MDM2 blockade did not enhance podocyte apoptosis but rather prevented aberrant nuclear divisions and death of aneuploid podocytes, i.e. mitotic catastrophe. Accordingly, MDM2 blockade induced p21 and prevented podocyte mitosis in-vivo while TUNEL+ apoptotic podocytes were not detected. Thus, mitotic catastrophe is a previously unrecognized variant of podocyte loss where MDM2 promotes podocytes to complete the cell cycle, which in the absence of cytokinesis, leads to podocyte aneuploidy and death. Furthermore, delayed MDM2 blockade also reduced plasma creatinine levels, BUN, tubular atrophy, interstitial leukocyte numbers and cytokine expression as well as interstitial fibrosis. Together, MDM2 blockade with nutlin-3a could be a novel therapeutic strategy to prevent renal inflammation, podocyte loss, glomerulosclerosis, proteinuria, and progressive kidney disease. In conclusion, therapeutic MDM2 blockade may hold the risk of impaired epithelial healing in AKI. On the other hand it may delay or halt the progression of glomerular disorders to CKD by reducing renal inflammation and by directly protecting podocytes from cell death by mitotic catastrophe.

2 citations

Journal ArticleDOI
TL;DR: The development of susceptibility to secondary pathogenic infections in the oral cavity during HIV infection is likely to result from or coincide with deterioration of the local mucosal immune system.
Abstract: Background The development of susceptibility to secondary pathogenic infections in the oral cavity during HIV infection is likely to result from or coincide with deterioration of the local mucosal immune system. Methods We have utilized the SIV model to investigate the kinetics and magnitude of oral pathogenesis during systemic dissemination of intravenously inoculated SIVmac251. Results Viral replication was detected in oropharyngeal lymph nodes at 6 weeks post-infection and shown to be coincident with a broad scale loss of growth factor receptor transcription in the oral mucosa, providing multiple avenues for blocking the normal activity of apoptosis inhibitors that function through Bcl2- and p53-dependent pathways. Conclusions Our findings suggest that the normal balance between cell death and regeneration may be rapidly disrupted in the oral mucosa during the early stages of immunodeficiency virus infection, setting the stage for continuing deterioration of immune function and the development of susceptibility to secondary infections.

1 citations

References
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Journal ArticleDOI
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.

8,339 citations

Journal ArticleDOI
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.
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

Journal ArticleDOI
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.
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

Journal ArticleDOI
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.
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

Journal ArticleDOI
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