Mdm2

Summary

Gene Symbol: Mdm2
Description: MDM2 proto-oncogene
Alias: E3 ubiquitin-protein ligase Mdm2, MDM2 oncogene, E3 ubiquitin protein ligase, MDM2 proto-oncogene, E3 ubiquitin protein ligase, Mdm2 p53 binding protein homolog, double minute 2, p53 E3 ubiquitin protein ligase, transformed mouse 3T3 cell double minute 2
Species: rat
Products:     Mdm2

Top Publications

  1. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296-9 pubmed
    ..The Mdm2 oncoprotein is a potent inhibitor of p53...
  2. Lin H, Wang L, Hu Y, Altuwaijri S, Chang C. Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J. 2002;21:4037-48 pubmed
    ..Here we show that Akt and Mdm2 form a complex with AR and promote phosphorylation-dependent AR ubiquitylation, resulting in AR degradation by the ..
  3. Bernardi R, Scaglioni P, Bergmann S, Horn H, Vousden K, Pandolfi P. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol. 2004;6:665-72 pubmed
    ..PML was recently shown to interact with the p53 ubiquitin-ligase Mdm2 (refs 4-6); however, the mechanism by which PML regulates Mdm2 remains unclear...
  4. 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.
  5. Horn H, Vousden K. Cooperation between the ribosomal proteins L5 and L11 in the p53 pathway. Oncogene. 2008;27:5774-84 pubmed publisher
    b>MDM2 is a ubiquitin ligase that plays a key role in regulating the stability of the p53 tumor suppressor protein...
  6. Lee J, Kim H, Lee S, Kim K. Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death. J Cell Sci. 2007;120:2259-71 pubmed
    ..Cdk5 mediates disruption of the interaction between p53 and Hdm2 (also known as Mdm2), and prevents Hdm2-induced p53 ubiquitylation and downregulation...
  7. Saito A, Hayashi T, Okuno S, Nishi T, Chan P. Modulation of p53 degradation via MDM2-mediated ubiquitylation and the ubiquitin-proteasome system during reperfusion after stroke: role of oxidative stress. J Cereb Blood Flow Metab. 2005;25:267-80 pubmed
    ..Degradation of p53 hinders its role in apoptosis regulation. Recent studies have shown that MDM2-mediated ubiquitylation and the ubiquitin-proteasome system are critical regulating systems of p53 ubiquitylation...
  8. Kurki S, Latonen L, Laiho M. Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization. J Cell Sci. 2003;116:3917-25 pubmed
    b>Mdm2 is a nucleoplasmic and nucleolar protein interacting with p53 and alternative reading frame (ARF) tumor suppressor proteins...
  9. Fang S, Jensen J, Ludwig R, Vousden K, Weissman A. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem. 2000;275:8945-51 pubmed
    b>Mdm2 has been shown to regulate p53 stability by targeting the p53 protein for proteasomal degradation. We now report that Mdm2 is a ubiquitin protein ligase (E3) for p53 and that its activity is dependent on its RING finger...

More Information

Publications62

  1. Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997;420:25-7 pubmed
    ..p53 was polyubiquitinated in the presence of E1, UbcH5 as E2 and MDM2 oncoprotein...
  2. Song X, Raman D, Gurevich E, Vishnivetskiy S, Gurevich V. Visual and both non-visual arrestins in their "inactive" conformation bind JNK3 and Mdm2 and relocalize them from the nucleus to the cytoplasm. J Biol Chem. 2006;281:21491-9 pubmed
    ..two proteins involved in "life-and-death" decisions in the cell, the kinase JNK3 and the ubiquitin ligase Mdm2. In human embryonic kidney 293 cells green fluorescent protein (GFP)-JNK3 and GFP-Mdm2 predominantly localize in ..
  3. Li L, Zhao D, Wei H, Yao L, Dang Y, Amjad A, et al. REG? deficiency promotes premature aging via the casein kinase 1 pathway. Proc Natl Acad Sci U S A. 2013;110:11005-10 pubmed publisher
    ..Interestingly, a massive increase of p53 in REG?(-/-) tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced...
  4. Bouleau S, Grimal H, Rincheval V, Godefroy N, Mignotte B, Vayssiere J, et al. FGF1 inhibits p53-dependent apoptosis and cell cycle arrest via an intracrine pathway. Oncogene. 2005;24:7839-49 pubmed
    ..FGF1 increases MDM2 expression at both mRNA and protein levels...
  5. Lohrum M, Ashcroft M, Kubbutat M, Vousden K. Identification of a cryptic nucleolar-localization signal in MDM2. Nat Cell Biol. 2000;2:179-81 pubmed
  6. Grochola L, Müller T, Bond G, Taubert H, Udelnow A, Wurl P. MDM2 SNP309 associates with accelerated pancreatic adenocarcinoma formation. Pancreas. 2010;39:76-80 pubmed publisher
    The G-allele of a single nucleotide polymorphism in the promoter of the MDM2 gene (MDM2 SNP309, T/G) associates with the acceleration of tumor formation and an increased risk for developing various malignancies...
  7. Lee Y, Wan J, Kim B, Bae M, Song B. Ubiquitin-dependent degradation of p53 protein despite phosphorylation at its N terminus by acetaminophen. J Pharmacol Exp Ther. 2006;317:202-8 pubmed
    ..Immunoblot analysis of the immunoprecipitated p53 revealed that increased amounts of murine double minute 2 (mdm2) and ubiquitin were bound to p53 during its degradation...
  8. Chen D, Zhang Z, Li M, Wang W, Li Y, Rayburn E, et al. Ribosomal protein S7 as a novel modulator of p53-MDM2 interaction: binding to MDM2, stabilization of p53 protein, and activation of p53 function. Oncogene. 2007;26:5029-37 pubmed
    As a major negative regulator of p53, the MDM2 oncogene plays an important role in carcinogenesis and tumor progression. MDM2 promotes p53 proteasomal degradation and negatively regulates p53 function...
  9. Zhang Y, Xiong Y. Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. Mol Cell. 1999;3:579-91 pubmed
    ..the nucleolus via a sequence within the exon 2-encoded C-terminal domain and is induced to leave the nucleolus by MDM2. ARF forms nuclear bodies with MDM2 and p53 and blocks p53 and MDM2 nuclear export...
  10. Fu X, Yucer N, Liu S, Li M, Yi P, Mu J, et al. RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. Proc Natl Acad Sci U S A. 2010;107:4579-84 pubmed publisher
    ..cells, the tumor suppressor p53 is maintained at low levels by ubiquitin-mediated proteolysis mainly through Mdm2. In response to DNA damage, p53 is stabilized and becomes activated to turn on transcriptional programs that are ..
  11. Wang J, He X, Luo Y, Yarbrough W. A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2. Biochem J. 2006;393:489-501 pubmed
    ..ARF binds MDM2 (murine double minute 2) and releases p53 from inhibition by MDM2, resulting in stabilization, accumulation and activation of p53...
  12. Allende Vega N, Saville M, Meek D. Transcription factor TAFII250 promotes Mdm2-dependent turnover of p53. Oncogene. 2007;26:4234-42 pubmed
    The p53 tumour suppressor is regulated mainly by Mdm2, an E3 ubiquitin ligase that promotes the ubiquitylation and proteasome-mediated degradation of p53...
  13. Chen B, Longtine M, Sadovsky Y, Nelson D. Hypoxia downregulates p53 but induces apoptosis and enhances expression of BAD in cultures of human syncytiotrophoblasts. Am J Physiol Cell Physiol. 2010;299:C968-76 pubmed publisher
  14. Mocanu M, Yellon D. p53 down-regulation: a new molecular mechanism involved in ischaemic preconditioning. FEBS Lett. 2003;555:302-6 pubmed
    ..p53 is inactivated possibly via phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-murine double minute 2 (Mdm2) phosphorylation...
  15. Odiete O, Konik E, Sawyer D, Hill M. Type 1 diabetes mellitus abrogates compensatory augmentation of myocardial neuregulin-1?/ErbB in response to myocardial infarction resulting in worsening heart failure. Cardiovasc Diabetol. 2013;12:52 pubmed publisher
    ..Myocardial protein expression of NRG-1?, ErbB2 and ErbB4 receptors, and MDM2 (a downstream signaling pathway induced by NRG-1 that has been implicated in cell survival) was assessed in the ..
  16. Malmlöf M, Roudier E, Hogberg J, Stenius U. MEK-ERK-mediated phosphorylation of Mdm2 at Ser-166 in hepatocytes. Mdm2 is activated in response to inhibited Akt signaling. J Biol Chem. 2007;282:2288-96 pubmed
    b>Mdm2 inactivates the tumor suppressor p53 and Akt has been shown to be a major activator of Mdm2 in many cell types. We have investigated the regulation of Mdm2 in hepatocytes...
  17. Nair V, McNaught K, Gonzalez Maeso J, Sealfon S, Olanow C. p53 mediates nontranscriptional cell death in dopaminergic cells in response to proteasome inhibition. J Biol Chem. 2006;281:39550-60 pubmed
    ..Further, there was no increase in Puma or Bax mRNA and p53 co-immunoprecipitated with Bcl-xL and Mdm2. These findings suggest that p53 mediates cell death by way of a direct mitochondrial effect in this model...
  18. Barzalobre Gerónimo R, Raúl B, Flores López L, Antonio F, Baiza Gutman L, Arturo B, et al. Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5F cells. Mol Cell Biochem. 2015;405:257-64 pubmed publisher
    ..Murine double minute 2 (Mdm2) induces the degradation of p53 and thereby protects cells from apoptosis...
  19. Oliner J, Kinzler K, Meltzer P, George D, Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992;358:80-3 pubmed
    ..b>MDM2 is a strong candidate for one such cellular protein; the MDM2 gene was originally identified by virtue of its ..
  20. Eberspächer E, Werner C, Engelhard K, Pape M, Laacke L, Winner D, et al. Long-term effects of hypothermia on neuronal cell death and the concentration of apoptotic proteins after incomplete cerebral ischemia and reperfusion in rats. Acta Anaesthesiol Scand. 2005;49:477-87 pubmed
    ..Therefore, after cerebral ischemia, hypothermia has the sustained neuroprotective potential to shift apoptosis-related proteins towards neuronal cell survival. ..
  21. 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
    ..In our previous studies, we have found that Daxx forms a complex with the E3 ubiquitin ligase Mdm2 and the de-ubiquitinase Hausp...
  22. Brady S, Yu Y, Maggi L, Weber J. ARF impedes NPM/B23 shuttling in an Mdm2-sensitive tumor suppressor pathway. Mol Cell Biol. 2004;24:9327-38 pubmed
    ..The Mdm2 oncogene outcompetes NPM/B23 for ARF binding, and introduction of Mdm2 reverses ARF's p53-independent properties: ..
  23. Hui L, Abbas T, Pielak R, Joseph T, Bargonetti J, Foster D. Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53. Mol Cell Biol. 2004;24:5677-86 pubmed
    ..Elevated expression of PLD also led to increased expression of the p53 E3 ubiquitin ligase MDM2 and increased turnover of p53...
  24. Jiang Y, Yang W, Zhou Y, Ma L. Up-regulation of murine double minute clone 2 (MDM2) gene expression in rat brain after morphine, heroin, and cocaine administrations. Neurosci Lett. 2003;352:216-20 pubmed
    ..the effects of treatments with different addictive drugs on gene expression of murine double minute clone 2 (MDM2), a key negative regulator of p53 and an important mediator in cell apoptosis...
  25. Bothner B, Aubin Y, Kriwacki R. Peptides derived from two dynamically disordered proteins self-assemble into amyloid-like fibrils. J Am Chem Soc. 2003;125:3200-1 pubmed
    ..The beta-strand-containing fibrils formed from these peptides may allow the directed assembly of decorated fibrils with applications as biological nanostructures. ..
  26. Okishiro M, Kim S, Tsunashima R, Nakayama T, Shimazu K, Shimomura A, et al. MDM2 SNP309 and TP53 R72P associated with severe and febrile neutropenia in breast cancer patients treated with 5-FU/epirubicin/cyclophosphamide. Breast Cancer Res Treat. 2012;132:947-53 pubmed publisher
    The aim of this study was to investigate the association of two genetic polymorphisms, MDM2 SNP309 and TP53 R72P, with incidence of neutropenia in breast cancer patients treated with 5-FU/epirubicin/cyclophosphamide (FEC)...
  27. Picksley S, Vojtesek B, Sparks A, Lane D. Immunochemical analysis of the interaction of p53 with MDM2;--fine mapping of the MDM2 binding site on p53 using synthetic peptides. Oncogene. 1994;9:2523-9 pubmed
    The function of p53 is modulated by binding to a number of cellular and viral proteins, such as MDM2 and SV40 large T antigen...
  28. Hashimoto T, Ichiki T, Ikeda J, Narabayashi E, Matsuura H, Miyazaki R, et al. Inhibition of MDM2 attenuates neointimal hyperplasia via suppression of vascular proliferation and inflammation. Cardiovasc Res. 2011;91:711-9 pubmed publisher
    ..p53 is negatively regulated by murine double minute 2 (MDM2). A recently developed MDM2 inhibitor, nutlin-3, is a non-genotoxic activator of the p53 pathway...
  29. Wang X, Wang Y, Ma K, Chen X, Li W. MDM2 rs2279744 and TP53 rs1042522 polymorphisms associated with etoposide- and cisplatin-induced grade III/IV neutropenia in Chinese extensive-stage small-cell lung cancer patients. Oncol Res Treat. 2014;37:176-80 pubmed publisher
    ..g., neutropenia) are high. This study investigates the association of the MDM2 rs2279744 and TP53 rs1042522 single-nucleotide polymorphisms (SNPs) with EP-induced grade III/IV neutropenia and ..
  30. Bhattacharya S, Ray R, Johnson L. Role of polyamines in p53-dependent apoptosis of intestinal epithelial cells. Cell Signal. 2009;21:509-22 pubmed publisher
    Although p53 is known to play a critical role in the proliferation of gastrointestinal epithelia, the role of the Mdm2/p53 pathway in response to inducers of apoptosis in intestinal epithelial cells is unknown...
  31. Wu C, Miloslavskaya I, Demontis S, Maestro R, Galaktionov K. Regulation of cellular response to oncogenic and oxidative stress by Seladin-1. Nature. 2004;432:640-5 pubmed
    ..Following oncogenic and oxidative stress, Seladin-1 binds p53 amino terminus and displaces E3 ubiquitin ligase Mdm2 from p53, thus resulting in p53 accumulation...
  32. Boyd M, Vlatkovic N, Haines D. A novel cellular protein (MTBP) binds to MDM2 and induces a G1 arrest that is suppressed by MDM2. J Biol Chem. 2000;275:31883-90 pubmed
    The MDM2 protein, through its interaction with p53, plays an important role in the regulation of the G(1) checkpoint of the cell cycle...
  33. Iwasa H, Kudo T, Maimaiti S, Ikeda M, Maruyama J, Nakagawa K, et al. The RASSF6 tumor suppressor protein regulates apoptosis and the cell cycle via MDM2 protein and p53 protein. J Biol Chem. 2013;288:30320-9 pubmed publisher
    ..We reported previously that RASSF3 facilitates the degradation of MDM2, a major E3 ligase of p53, and stabilizes p53 to function as a tumor suppressor...
  34. Raz L, Zhang Q, Han D, Dong Y, De Sevilla L, Brann D. Acetylation of the pro-apoptotic factor, p53 in the hippocampus following cerebral ischemia and modulation by estrogen. PLoS ONE. 2011;6:e27039 pubmed publisher
    ..17?-E(2) also enhanced interaction of p53 with the ubiquitin ligase, Mdm2, increased ubiquitination of p53, and induced its down-regulation, as well as attenuated elevation of the p53 ..
  35. Del Terra E, Francesconi A, Donnini D, Curcio F, Ambesi Impiombato F. Thyrotropin effects on ultraviolet radiation-dependent apoptosis in FRTL-5 cells. Thyroid. 2003;13:747-53 pubmed
    ..Results indicate that Bcl2 and caspase-2 expression is enhanced, while bax, GADD45 and mdm-2 expression is reduced in irradiated cells. These data confirm that TSH plays a major role in regulating UV-induced apoptosis in FRTL-5 cells. ..
  36. Milkiewicz M, Roudier E, Doyle J, Trifonova A, Birot O, Haas T. Identification of a mechanism underlying regulation of the anti-angiogenic forkhead transcription factor FoxO1 in cultured endothelial cells and ischemic muscle. Am J Pathol. 2011;178:935-44 pubmed publisher
    ..Endogenous FoxO1 co-precipitated with the E3 ubiquitin ligase murine double minute-2 (Mdm2) in endothelial cells, and this interaction varied in direct relation to the extent of Akt and Mdm2 phosphorylation...
  37. Liu D, Ou L, Clemenson G, Chao C, Lutske M, Zambetti G, et al. Puma is required for p53-induced depletion of adult stem cells. Nat Cell Biol. 2010;12:993-8 pubmed publisher
    ..These findings suggest a key role of p53-dependent apoptosis in depleting adult stem cells after the accumulation of DNA damage, which leads to a decrease in tissue regeneration. ..
  38. Mesaeli N, Phillipson C. Impaired p53 expression, function, and nuclear localization in calreticulin-deficient cells. Mol Biol Cell. 2004;15:1862-70 pubmed
    ..techniques, we showed that observed changes in p53 in the crt-/- cells are due to the nuclear accumulation of Mdm2 (murine double minute gene)...
  39. Yang Z, Ge J, Yin W, Shen H, Liu H, Guo Y. [The expression of p53, MDM2 and Ref1 gene in cultured retina neurons of SD rats treated with vitamin B1 and/or elevated pressure]. Yan Ke Xue Bao. 2004;20:259-63 pubmed
    To investigate the expression of p53, MDM2 and Ref1 gene in cultured retina neurons of SD rats treated with Vitamin B1 and (or) elevated pressure...
  40. Dongiovanni P, Fracanzani A, Cairo G, Megazzini C, Gatti S, Rametta R, et al. Iron-dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis. Am J Pathol. 2010;176:1006-17 pubmed publisher
    ..revealed that iron downregulated, whereas deferoxamine upregulated, mRNA levels of mouse double minute gene 2 (MDM2), the ubiquitin ligase involved in the degradation of the oncosuppressor p53...
  41. 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
    ..examines the role of Delta(9)-THC in regulating the p53 post-translational modifier proteins, Murine double minute (Mdm2) and Small Ubquitin-like MOdifier protein 1 (SUMO-1) in cortical neurons...
  42. Li X, Baillie G, Houslay M. Mdm2 directs the ubiquitination of beta-arrestin-sequestered cAMP phosphodiesterase-4D5. J Biol Chem. 2009;284:16170-82 pubmed publisher
    ..small interference RNA knockdown studies indicate that a beta-arrestin-scaffolded pool of the E3-ubiquitin ligase, Mdm2, mediates PDE4D5 ubiquitination...
  43. Fumagalli M, Bonfanti E, Daniele S, Zappelli E, Lecca D, Martini C, et al. The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization. Glia. 2015;63:2327-39 pubmed publisher
    ..Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of the onco-suppressor p53 protein...
  44. Zhang Y, Xiong Y, Yarbrough W. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998;92:725-34 pubmed
    ..We show here that ARF binds to MDM2 and promotes the rapid degradation of MDM2...
  45. Sharp D, Kratowicz S, Sank M, George D. Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. J Biol Chem. 1999;274:38189-96 pubmed
    The MDM2 oncoprotein has transforming potential that can be activated by overexpression, and it represents a critical regulator of the p53 tumor suppressor protein...
  46. Youssef G, Ono M, Brown S, Kinsler V, Sebire N, Harper J, et al. Identifying a hyperkeratosis signature in autosomal recessive congenital ichthyosis: Mdm2 inhibition prevents hyperkeratosis in a rat ARCI model. J Invest Dermatol. 2014;134:858-861 pubmed publisher
  47. Ye C, Tang H, Zhao Z, Lei C, You C, Zhang J, et al. MDM2 mediates fibroblast activation and renal tubulointerstitial fibrosis via a p53-independent pathway. Am J Physiol Renal Physiol. 2017;312:F760-F768 pubmed publisher
    It is well recognized that murine double minute gene 2 (MDM2) plays a critical role in cell proliferation and inflammatory processes during tumorigenesis...
  48. Buschmann T, Lin Y, Aithmitti N, Fuchs S, Lu H, Resnick Silverman L, et al. Stabilization and activation of p53 by the coactivator protein TAFII31. J Biol Chem. 2001;276:13852-7 pubmed
    Regulation of the stability of p53 is key to its tumor-suppressing activities. mdm2 directly binds to the amino-terminal region of p53 and targets it for degradation through the ubiquitin-proteasome pathway...
  49. Li Q, Lozano G. Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy. Clin Cancer Res. 2013;19:34-41 pubmed publisher
    ..dampen p53 activities via overexpression of p53-negative regulators, in particular 2 structurally related proteins, Mdm2 and Mdm4...
  50. Liu Y, Chen Y, Lu X, Wang Y, Duan Y, Cheng C, et al. SCYL1BP1 modulates neurite outgrowth and regeneration by regulating the Mdm2/p53 pathway. Mol Biol Cell. 2012;23:4506-14 pubmed publisher
    ..Furthermore, SCYL1BP1 can directly induce Mdm2 transcription, whereas inhibiting the function of Mdm2 by specific small interfering RNAs results in partial rescue ..
  51. Okamoto K, Li H, Jensen M, Zhang T, Taya Y, Thorgeirsson S, et al. Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell. 2002;9:761-71 pubmed
    ..Interestingly, cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216...
  52. 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
    ..The upstream regulation of caspases-2 includes p53, which was increased; the p53 negative regulator, Mdm2, was decreased by anti-PMN treatment during cerulein pancreatitis...
  53. Gopinathan L, Hannon D, Peters J, Vanden Heuvel J. Regulation of peroxisome proliferator-activated receptor-alpha by MDM2. Toxicol Sci. 2009;108:48-58 pubmed publisher
    ..In this study, Murine Double Minute 2 (MDM2), an E3 ubiquitin ligase, is identified as a PPARalpha-interacting protein that regulates PPARalpha ..