proto oncogene proteins c mdm2

Summary

Summary: An E3 UBIQUITIN LIGASE that interacts with and inhibits TUMOR SUPPRESSOR PROTEIN P53. Its ability to ubiquitinate p53 is regulated by TUMOR SUPPRESSOR PROTEIN P14ARF.

Top Publications

  1. Gryshchenko I, Hofbauer S, Stoecher M, Daniel P, Steurer M, Gaiger A, et al. MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia. J Clin Oncol. 2008;26:2252-7 pubmed publisher
    ..The MDM2 SNP309 genotype influencing MDM2 expression levels was identified as an additional independent risk factor in B-CLL. Targeting MDM2-p53 interactions might emerge as a successful treatment strategy for B-CLL. ..
  2. Mayo L, Dixon J, Durden D, Tonks N, Donner D. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem. 2002;277:5484-9 pubmed
    ..p53 induces PTEN gene expression, and here it is shown that PTEN protects p53, indicating that a positive feedback loop may amplify the cellular response to stress, damage, and cancer. ..
  3. Marcel V, Palmero E, Falagan Lotsch P, Martel Planche G, Ashton Prolla P, Olivier M, et al. TP53 PIN3 and MDM2 SNP309 polymorphisms as genetic modifiers in the Li-Fraumeni syndrome: impact on age at first diagnosis. J Med Genet. 2009;46:766-72 pubmed publisher
  4. Jenkins L, Yamaguchi H, Hayashi R, Cherry S, Tropea J, Miller M, et al. Two distinct motifs within the p53 transactivation domain bind to the Taz2 domain of p300 and are differentially affected by phosphorylation. Biochemistry. 2009;48:1244-55 pubmed publisher
    ..However, the more negative value of DeltaC(p) for Taz2 binding to the first (-330 cal/(mol.K)) compared to the second site (-234 cal/(mol.K)) suggests that the importance of nonpolar and polar interactions differs between the two sites. ..
  5. Carotti A, Macchiarulo A, Giacchè N, Pellicciari R. Targeting the conformational transitions of MDM2 and MDMX: insights into key residues affecting p53 recognition. Proteins. 2009;77:524-35 pubmed publisher
    ..The results of this study shed further light on different p53 recognition in MDM2 and MDMX and may prove useful for the design and identification of new potent and selective synthetic modulators of p53-MDM2/MDMX interactions. ..
  6. Pazgier M, Liu M, Zou G, Yuan W, Li C, Li C, et al. Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc Natl Acad Sci U S A. 2009;106:4665-70 pubmed publisher
  7. Groehler A, Lannigan D. A chromatin-bound kinase, ERK8, protects genomic integrity by inhibiting HDM2-mediated degradation of the DNA clamp PCNA. J Cell Biol. 2010;190:575-86 pubmed publisher
    ..Our results reveal an unanticipated mechanism to control PCNA levels in normal cycling mammary epithelial cells and implicate ERK8 in the regulation of genomic stability. ..
  8. Kruse J, Gu W. Modes of p53 regulation. Cell. 2009;137:609-22 pubmed publisher
    ..To reconcile these differences, we propose that antirepression, the release of p53 from repression by factors such as Mdm2 and MdmX, is a key step in the physiological activation of p53. ..
  9. Long J, Parkin B, Ouillette P, Bixby D, Shedden K, Erba H, et al. Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood. 2010;116:71-80 pubmed publisher

More Information

Publications62

  1. Vaseva A, Marchenko N, Moll U. The transcription-independent mitochondrial p53 program is a major contributor to nutlin-induced apoptosis in tumor cells. Cell Cycle. 2009;8:1711-9 pubmed
    ..Moreover, at least in some tumors the transcriptional p53 activities in net balance not only are dispensable for the apoptotic Nutlin response, but appear to actively block its therapeutic effect. ..
  2. Grässlin A, Amoreira C, Baldridge K, Robinson J. Thermodynamic and computational studies on the binding of p53-derived peptides and peptidomimetic inhibitors to HDM2. Chembiochem. 2009;10:1360-8 pubmed publisher
    ..The formation of these hydrogen bonds upon helix folding could contribute significantly to the enhanced enthalpy observed in binding of the linear peptide to HDM2. ..
  3. Xiong X, Wang M, Wang L, Liu J, Zhao X, Tian Z, et al. Risk of MDM2 SNP309 alone or in combination with the p53 codon 72 polymorphism in acute myeloid leukemia. Leuk Res. 2009;33:1454-8 pubmed publisher
    ..These results suggest that the MDM2 SNP309 homozygous GG genotype may be a genetic susceptibility factor in the pathogenesis of AML. ..
  4. Madhumalar A, Lee H, Brown C, Lane D, Verma C. Design of a novel MDM2 binding peptide based on the p53 family. Cell Cycle. 2009;8:2828-36 pubmed
    ..Computations also reveal that this peptide is a dual inhibitor, binding also to MDMX. The computed affinity of the new peptide has been validated against MDM2 using fluorescence-based thermal shift assays. ..
  5. Ferreon J, Lee C, Arai M, Martinez Yamout M, Dyson H, Wright P. Cooperative regulation of p53 by modulation of ternary complex formation with CBP/p300 and HDM2. Proc Natl Acad Sci U S A. 2009;106:6591-6 pubmed publisher
    ..After cellular stress and DNA damage, p53 becomes phosphorylated at T18 and other residues in the AD1 region, releases HDM2 and binds preferentially to CBP/p300, leading to stabilization and activation of p53. ..
  6. Nechushtan H, Hamburger T, Mendelson S, Kadouri L, Sharon N, Pikarsky E, et al. Effects of the single nucleotide polymorphism at MDM2 309 on breast cancer patients with/without BRCA1/2 mutations. BMC Cancer. 2009;9:60 pubmed publisher
    ..MDM2SNP309G/G main effect on BRCA1/2 positive mutation carriers is linked to its effect on patients survival. Further research is needed in order to understand the reason for this difference. ..
  7. Srivastava S, Beck B, Wang W, Czarna A, Holak T, Dömling A. Rapid and efficient hydrophilicity tuning of p53/mdm2 antagonists. J Comb Chem. 2009;11:631-9 pubmed publisher
    ..Arrays of amides were synthesized with improved hydrophilicity and retainment and/or improvement of p53/mdm2 inhibitory activity. ..
  8. Wang X, Yang J, Ho B, Yang Y, Huang Z, Zhang Z, et al. Interaction of Helicobacter pylori with genetic variants in the MDM2 promoter, is associated with gastric cancer susceptibility in Chinese patients. Helicobacter. 2009;14:114-9 pubmed publisher
    ..There was no significant difference in age at diagnosis among genotypes. The MDM2 promoter SNP309 is associated with the presence of gastric cancer in Chinese patients especially those with H. pylori infection. ..
  9. Chen X, Sturgis E, Lei D, Dahlstrom K, Wei Q, Li G. Human papillomavirus seropositivity synergizes with MDM2 variants to increase the risk of oral squamous cell carcinoma. Cancer Res. 2010;70:7199-208 pubmed publisher
    ..Taken together, our results indicate that the risk of OSCC associated with HPV16 L1 seropositivity is modified by MDM2 promoter polymorphisms...
  10. Verma R, Rigatti M, Belinsky G, Godman C, Giardina C. DNA damage response to the Mdm2 inhibitor nutlin-3. Biochem Pharmacol. 2010;79:565-74 pubmed publisher
    ..Although this effect may suppress illegitimate homologous recombination repair, it may also increase the risk of clastogenic events. ..
  11. Li L, Tao Q, Jin H, Van Hasselt A, Poon F, Wang X, et al. The tumor suppressor UCHL1 forms a complex with p53/MDM2/ARF to promote p53 signaling and is frequently silenced in nasopharyngeal carcinoma. Clin Cancer Res. 2010;16:2949-58 pubmed publisher
  12. Zhou Q, Yan B, Hu X, Li X, Zhang J, Fang J. Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin. Mol Cancer Ther. 2009;8:1684-91 pubmed publisher
    ..These findings provide a new sight into the mechanisms that luteolin is against cancer cells, and suggest that molecular targeting of E-cadherin by luteolin may be a useful strategy for treatment of invasive prostate cancers. ..
  13. Phillips C, Gerbing R, Alonzo T, Perentesis J, Harley I, Meshinchi S, et al. MDM2 polymorphism increases susceptibility to childhood acute myeloid leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2010;55:248-53 pubmed publisher
    ..The variant SNP 309 influences susceptibility to pediatric AML, but does not impact overall response to therapy. ..
  14. Wu Q, Hu H, Lan J, Emenari C, Wang Z, Chang K, et al. PML3 Orchestrates the Nuclear Dynamics and Function of TIP60. J Biol Chem. 2009;284:8747-59 pubmed publisher
    ..Thus, PML3 orchestrates the distribution, dynamics, and function of TIP60. Our findings suggest a novel regulatory mechanism by which the PML3 and TIP60 tumor suppressors cooperate to ensure genomic stability. ..
  15. Kojima K, Shimanuki M, Shikami M, Andreeff M, Nakakuma H. Cyclin-dependent kinase 1 inhibitor RO-3306 enhances p53-mediated Bax activation and mitochondrial apoptosis in AML. Cancer Sci. 2009;100:1128-36 pubmed publisher
  16. Impicciatore G, Sancilio S, Miscia S, Di Pietro R. Nutlins and ionizing radiation in cancer therapy. Curr Pharm Des. 2010;16:1427-42 pubmed
  17. Lavelin I, Beer A, Kam Z, Rotter V, Oren M, Navon A, et al. Discovery of novel proteasome inhibitors using a high-content cell-based screening system. PLoS ONE. 2009;4:e8503 pubmed publisher
    ..The special features of the current screen, compared to those of other approaches are discussed. ..
  18. Daugaard S, Christensen L, Høgdall E. Markers aiding the diagnosis of chondroid tumors: an immunohistochemical study including osteonectin, bcl-2, cox-2, actin, calponin, D2-40 (podoplanin), mdm-2, CD117 (c-kit), and YKL-40. APMIS. 2009;117:518-25 pubmed publisher
    ..A convincing immunoreactivity for calponin and/or actin in chondromyxoid fibromas and chondroblastomas may also be helpful in differentiating these tumors from chondrosarcomas. ..
  19. Lau J, Lew Q, Diribarne G, Michels A, Dey A, Bensaude O, et al. Ubiquitination of HEXIM1 by HDM2. Cell Cycle. 2009;8:2247-54 pubmed
    ..Our results demonstrate that HDM2 functions as a specific E3 ubiquitin ligase for HEXIM1, suggesting a possible role for HEXIM1 ubiquitination in the regulation of P-TEFb activity. ..
  20. Lipton J, Ellis S. Diamond Blackfan anemia 2008-2009: broadening the scope of ribosome biogenesis disorders. Curr Opin Pediatr. 2010;22:12-9 pubmed publisher
    ..The description of DBA as a ribosomopathy has provided a context for scientific inquiry analogous to the description of Fanconi anemia as a disorder of DNA repair. ..
  21. Chi X, Kim J, Lee Y, Lee J, Lee K, Wee H, et al. Runt-related transcription factor RUNX3 is a target of MDM2-mediated ubiquitination. Cancer Res. 2009;69:8111-9 pubmed publisher
  22. Li Q, Xu J, Wang W, Cao X, Chen Q, Tang F, et al. Twist1-mediated adriamycin-induced epithelial-mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin Cancer Res. 2009;15:2657-65 pubmed publisher
  23. Singh A, Evens A, Prachand S, Gordon L. Motexafin gadolinium enhances p53-Mdm2 interactions, reducing p53 and downstream targets in lymphoma cell lines. Anticancer Res. 2010;30:1131-6 pubmed
    ..Our data are consistent with a pathway of cell death that is independent of p53-mediated induction of PUMA; the cellular response to reduce p53 represents a cell survival adjustment to ROS-mediated stress. ..
  24. Groskreutz D, Monick M, Yarovinsky T, Powers L, Quelle D, Varga S, et al. Respiratory syncytial virus decreases p53 protein to prolong survival of airway epithelial cells. J Immunol. 2007;179:2741-7 pubmed
    ..These findings reveal that RSV decreases p53 by enhancing Akt/Mdm2-mediated p53 degradation, thereby delaying apoptosis and prolonging survival of airway epithelial cells. ..
  25. Lu T, Chen C, Lee M, Ho T, Leung Y, Hung D, et al. Methylmercury chloride induces alveolar type II epithelial cell damage through an oxidative stress-related mitochondrial cell death pathway. Toxicol Lett. 2010;194:70-8 pubmed publisher
    ..These results suggest that MeHgCl activates an oxidative stress-induced mitochondrial cell death in alveolar epithelial cells. ..
  26. Ito R, Kanno H, Takahashi A, Matsumoto R, Kobayashi N, Yoshida T, et al. Efficient growth inhibition of human osteosarcoma cells using a peptide derived from the MDM-2-binding site of p53. Protein Pept Lett. 2010;17:610-5 pubmed
    ..We here demonstrate efficient growth inhibition of human osteosarcoma cells using a p53 peptide. Our result suggests that protein transduction therapy has significant potential as a novel therapeutic approach for osteosarcoma. ..
  27. Manna S, Bose J, Gangan V, Raviprakash N, Navaneetha T, Raghavendra P, et al. Novel derivative of benzofuran induces cell death mostly by G2/M cell cycle arrest through p53-dependent pathway but partially by inhibition of NF-kappaB. J Biol Chem. 2010;285:22318-27 pubmed publisher
    ..Thus, this novel benzofuran lignan derivative can be effective chemopreventive or chemotherapeutic agent against malignant T-cells. ..
  28. Ishimura A, Terashima M, Kimura H, Akagi K, Suzuki Y, Sugano S, et al. Jmjd2c histone demethylase enhances the expression of Mdm2 oncogene. Biochem Biophys Res Commun. 2009;389:366-71 pubmed publisher
    ..These results indicate that Mdm2 oncogene is a downstream target of Jmjd2c and may play an important role in Jmjd2c-mediated oncogenesis. ..
  29. Cui Y, Kerby A, McDuff F, Ye H, Turner S. NPM-ALK inhibits the p53 tumor suppressor pathway in an MDM2 and JNK-dependent manner. Blood. 2009;113:5217-27 pubmed publisher
  30. Farhadieh R, Salardini A, Rees C, Russell P, Yang J, Smee R. Protein expression of epidermal growth factor receptor in laryngeal squamous cell carcinoma index tumors correlates with diagnosis of second primary tumors of the upper aero-digestive tract. Ann Surg Oncol. 2009;16:2888-94 pubmed publisher
    ..Examination of the expression of EGFR by the primary tumor could have potential clinical benefits because this study suggests that it may become a vital biomarker for patients who are most at risk of developing SPTs. ..
  31. Mu R, Qi Q, Gu H, Wang J, Yang Y, Rong J, et al. Involvement of p53 in oroxylin A-induced apoptosis in cancer cells. Mol Carcinog. 2009;48:1159-69 pubmed publisher
    ..This indicated that oroxylin A could be served as a potential, novel agent candidate for cancer therapy. ..
  32. Sashida G, Liu Y, Elf S, Miyata Y, Ohyashiki K, Izumi M, et al. ELF4/MEF activates MDM2 expression and blocks oncogene-induced p16 activation to promote transformation. Mol Cell Biol. 2009;29:3687-99 pubmed publisher
    ..Thus, ELF4/MEF promotes tumorigenesis by inhibiting both the p53 and p16/Rb pathways. ..
  33. Economopoulos K, Sergentanis T. Differential effects of MDM2 SNP309 polymorphism on breast cancer risk along with race: a meta-analysis. Breast Cancer Res Treat. 2010;120:211-6 pubmed publisher
    ..MDM2 SNP309 represents a risk factor for breast cancer in Chinese women but not in non-Chinese women. This phenomenon is analogous to that described in the context of lung cancer. ..
  34. Solozobova V, Rolletschek A, Blattner C. Nuclear accumulation and activation of p53 in embryonic stem cells after DNA damage. BMC Cell Biol. 2009;10:46 pubmed publisher
    ..However, if its activity is beneficial or required, p53 is allowed to accumulate in the nucleus and activates its target genes, even in embryonic stem cells. ..
  35. Xu B, Xu Z, Cheng G, Min Z, Mi Y, Zhang Z, et al. Association between polymorphisms of TP53 and MDM2 and prostate cancer risk in southern Chinese. Cancer Genet Cytogenet. 2010;202:76-81 pubmed publisher
    ..3% positive p53 expression, whereas subjects with 3-5 variants had 23.3% p53 expression (P = 0.39). These findings suggest that TP53 and MDM2 polymorphisms play a role in PCa susceptibility in southern Chinese Han population. ..
  36. Horvai A, Devries S, Roy R, O Donnell R, Waldman F. Similarity in genetic alterations between paired well-differentiated and dedifferentiated components of dedifferentiated liposarcoma. Mod Pathol. 2009;22:1477-88 pubmed publisher
    ..The relationship between genetic changes and presentation or grade may reflect differences in factors that control genomic instability or the background genotype of the tumor...
  37. Schrage Y, Lam S, Jochemsen A, Cleton Jansen A, Taminiau A, Hogendoorn P, et al. Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down-regulation and p16 overexpression inhibit cell growth in vitro. J Cell Mol Med. 2009;13:2843-52 pubmed publisher
    ..This suggests a role for the use of CDK4 inhibitors as a treatment of metastatic or inoperable high-grade chondrosarcoma. ..
  38. Geva Zatorsky N, Dekel E, Batchelor E, Lahav G, Alon U. Fourier analysis and systems identification of the p53 feedback loop. Proc Natl Acad Sci U S A. 2010;107:13550-5 pubmed publisher
    ..It seems to be a useful way to find the in vivo design of circuits and may be applied to other systems by monitoring their power spectrum in individual cells. ..
  39. Tabata N, Sakuma Y, Honda Y, Doi N, Takashima H, Miyamoto Sato E, et al. Rapid antibody selection by mRNA display on a microfluidic chip. Nucleic Acids Res. 2009;37:e64 pubmed publisher
    ..This method will facilitate high-throughput preparation of antibodies and identification of protein interactions in proteomic and therapeutic fields. ..
  40. Renouf B, Hollville E, Pujals A, Tetaud C, Garibal J, Wiels J. Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein-Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells. Leukemia. 2009;23:1557-63 pubmed publisher
    ..Most BL patients with wild-type p53 tumors could therefore benefit from treatment with nutlin-3, after a careful determination of the latency pattern of EBV in infected patients. ..
  41. Worrall E, Worrall L, Blackburn E, Walkinshaw M, Hupp T. The effects of phosphomimetic lid mutation on the thermostability of the N-terminal domain of MDM2. J Mol Biol. 2010;398:414-28 pubmed publisher
  42. Chung L, Lau S, Jiang Z, Loera S, Bedel V, Ji J, et al. Overlapping features between dedifferentiated liposarcoma and undifferentiated high-grade pleomorphic sarcoma. Am J Surg Pathol. 2009;33:1594-600 pubmed publisher
  43. Schmidt M, Tommiska J, Broeks A, van Leeuwen F, van T Veer L, Pharoah P, et al. Combined effects of single nucleotide polymorphisms TP53 R72P and MDM2 SNP309, and p53 expression on survival of breast cancer patients. Breast Cancer Res. 2009;11:R89 pubmed publisher
  44. Fernandez K, Serinagaoglu Y, Hammond S, Martin L, Martin P. Mice lacking dystrophin or alpha sarcoglycan spontaneously develop embryonal rhabdomyosarcoma with cancer-associated p53 mutations and alternatively spliced or mutant Mdm2 transcripts. Am J Pathol. 2010;176:416-34 pubmed publisher
  45. Tang J, Qu L, Pang M, Yang X. Daxx is reciprocally regulated by Mdm2 and Hausp. Biochem Biophys Res Commun. 2010;393:542-5 pubmed publisher
    ..These results reveal Mdm2 and Hausp as important regulators for Daxx functions by controlling Daxx ubiquitination and stability. ..
  46. Ma S, Yang Y, Wang C, Hui N, Gu L, Zhong H, et al. Endogenous human CaMKII inhibitory protein suppresses tumor growth by inducing cell cycle arrest and apoptosis through down-regulation of the phosphatidylinositide 3-kinase/Akt/HDM2 pathway. J Biol Chem. 2009;284:24773-82 pubmed publisher
  47. Gu L, Zhu N, Zhang H, Durden D, Feng Y, Zhou M. Regulation of XIAP translation and induction by MDM2 following irradiation. Cancer Cell. 2009;15:363-75 pubmed publisher
    ..Upregulation of XIAP in MDM2-overexpressing cancer cells in response to irradiation resulted in resistance of these cells to radiation-induced apoptosis. ..
  48. Nakamura Y, Do J, Yuan J, Odinokova I, Mareninova O, Gukovskaya A, et al. Inflammatory cells regulate p53 and caspases in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2010;298:G92-100 pubmed publisher
  49. Datta S, Bucks M, Koley D, Lim P, Savinov S. Functional profiling of p53-binding sites in Hdm2 and Hdmx using a genetic selection system. Bioorg Med Chem. 2010;18:6099-108 pubmed publisher
  50. Dudgeon D, Shinde S, Hua Y, Shun T, Lazo J, Strock C, et al. Implementation of a 220,000-compound HCS campaign to identify disruptors of the interaction between p53 and hDM2 and characterization of the confirmed hits. J Biomol Screen. 2010;15:766-82 pubmed publisher
  51. Gowran A, Murphy C, Campbell V. Delta(9)-tetrahydrocannabinol regulates the p53 post-translational modifiers Murine double minute 2 and the Small Ubiquitin MOdifier protein in the rat brain. FEBS Lett. 2009;583:3412-8 pubmed publisher
    ..We demonstrate that Delta(9)-THC decreased the SUMOylation of the CB(1) receptor. The data reveal a novel role for cannabinoid receptor activation in modulating the SUMO regulatory system. ..
  52. Ardito Marretta R, Barbaraci G. Digital control circuitry of cancer cell and its apoptosis. Mol Cell Biomech. 2009;6:175-89 pubmed
    ..Moreover, the cell fate is newly conceived and bound by the modified pulsing mechanism of p53. ..
  53. Lee Y, Lim J, Chun Y, Moon H, Lee M, Huang L, et al. Nutlin-3, an Hdm2 antagonist, inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated inactivation of HIF-1alpha. Carcinogenesis. 2009;30:1768-75 pubmed publisher
    ..The interplays among HIF-1alpha, Hdm2, FIH and p300 could be potential targets for treating tumors overexpressing HIF-1alpha. ..