Biology:Mdm2

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene.[1][2] Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation.

Discovery and expression in tumor cells

The murine double minute (mdm2) oncogene, which codes for the Mdm2 protein, was originally cloned, along with two other genes (mdm1 and mdm3) from the transformed mouse cell line 3T3-DM. Mdm2 overexpression, in cooperation with oncogenic Ras, promotes transformation of primary rodent fibroblasts, and mdm2 expression led to tumor formation in nude mice. The human homologue of this protein was later identified and is sometimes called Hdm2. Further supporting the role of mdm2 as an oncogene, several human tumor types have been shown to have increased levels of Mdm2, including soft tissue sarcomas and osteosarcomas as well as breast tumors. The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53. MDM2 depletion in the absence of p53 promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 (H3K27me3) and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation.[3]

An additional Mdm2 family member, Mdm4 (also called MdmX), has been discovered and is also an important negative regulator of p53.

MDM2 is also required for organ development and tissue homeostasis because unopposed p53 activation leads to p53-overactivation-dependent cell death, referred to as podoptosis. Podoptosis is caspase-independent and, therefore, different from apoptosis. The mitogenic role of MDM2 is also needed for wound healing upon tissue injury, while MDM2 inhibition impairs re-epithelialization upon epithelial damage. In addition, MDM2 has p53-independent transcription factor-like effects in nuclear factor-kappa beta (NFκB) activation. Therefore, MDM2 promotes tissue inflammation and MDM2 inhibition has potent anti-inflammatory effects in tissue injury. So, MDM2 blockade had mostly anti-inflammatory and anti-mitotic effects that can be of additive therapeutic efficacy in inflammatory and hyperproliferative disorders such as certain cancers or lymphoproliferative autoimmunity, such as systemic lupus erythematosus or crescentic glomerulonephritis.[4]

Ubiquitination target: p53

The key target of Mdm2 is the p53 tumor suppressor. Mdm2 has been identified as a p53 interacting protein that represses p53 transcriptional activity. Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53. Mdm2 is a p53 responsive gene—that is, its transcription can be activated by p53. Thus when p53 is stabilized, the transcription of Mdm2 is also induced, resulting in higher Mdm2 protein levels.

E3 ligase activity

The E3 ubiquitin ligase MDM2 is a negative regulator of the p53 tumor suppressor protein. MDM2 binds and ubiquitinates p53, facilitating it for degradation. p53 can induce transcription of MDM2, generating a negative feedback loop.[5] Mdm2 also acts as an E3 ubiquitin ligase, targeting both itself and p53 for degradation by the proteasome (see also ubiquitin). Several lysine residues in p53 C-terminus have been identified as the sites of ubiquitination, and it has been shown that p53 protein levels are downregulated by Mdm2 in a proteasome-dependent manner. Mdm2 is capable of auto-polyubiquitination, and in complex with p300, a cooperating E3 ubiquitin ligase, is capable of polyubiquitinating p53. In this manner, Mdm2 and p53 are the members of a negative feedback control loop that keeps the level of p53 low in the absence of p53-stabilizing signals. This loop can be interfered with by kinases and genes like p14arf when p53 activation signals, including DNA damage, are high.

Structure and function

The full-length transcript of the mdm2 gene encodes a protein of 491 amino acids with a predicted molecular weight of 56kDa. This protein contains several conserved structural domains including an N-terminal p53 interaction domain, the structure of which has been solved using x-ray crystallography. The Mdm2 protein also contains a central acidic domain (residues 230–300). The phosphorylation of residues within this domain appears to be important for regulation of Mdm2 function. In addition, this region contains nuclear export and import signals that are essential for proper nuclear-cytoplasmic trafficking of Mdm2. Another conserved domain within the Mdm2 protein is a zinc finger domain, the function of which is poorly understood.

Mdm2 also contains a C-terminal RING domain (amino acid residues 430–480), which contains a Cis3-His2-Cis3 consensus that coordinates two ions of zinc. These residues are required for zinc binding, which is essential for proper folding of the RING domain. The RING domain of Mdm2 confers E3 ubiquitin ligase activity and is sufficient for E3 ligase activity in Mdm2 RING autoubiquitination. The RING domain of Mdm2 is unique in that it incorporates a conserved Walker A or P-loop motif characteristic of nucleotide binding proteins, as well as a nucleolar localization sequence. The RING domain also binds specifically to RNA, although the function of this is poorly understood.

Regulation

There are several known mechanisms for regulation of Mdm2. One of these mechanisms is phosphorylation of the Mdm2 protein. Mdm2 is phosphorylated at multiple sites in cells. Following DNA damage, phosphorylation of Mdm2 leads to changes in protein function and stabilization of p53. Additionally, phosphorylation at certain residues within the central acidic domain of Mdm2 may stimulate its ability to target p53 for degradation. HIPK2 is a protein that regulates Mdm2 in this way. The induction of the p14arf protein, the alternate reading frame product of the p16INK4a locus, is also a mechanism of negatively regulating the p53-Mdm2 interaction. p14arf directly interacts with Mdm2 and leads to up-regulation of p53 transcriptional response. ARF sequesters Mdm2 in the nucleolus, resulting in inhibition of nuclear export and activation of p53, since nuclear export is essential for proper p53 degradation.

Inhibitors of the MDM2-p53 interaction include the cis-imidazoline analog nutlin.[6]

Levels and stability of Mdm2 are also modulated by ubiquitylation. Mdm2 auto ubiquitylates itself, which allows for its degradation by the proteasome. Mdm2 also interacts with a ubiquitin specific protease, USP7, which can reverse Mdm2-ubiquitylation and prevent it from being degraded by the proteasome. USP7 also protects from degradation the p53 protein, which is a major target of Mdm2. Thus Mdm2 and USP7 form an intricate circuit to finely regulate the stability and activity of p53, whose levels are critical for its function.

Interactions

Overview of signal transduction pathways involved in apoptosis.

Mdm2 has been shown to interact with:



Mdm2 p53-independent role

Mdm2 overexpression was shown to inhibit DNA double-strand break repair mediated through a novel, direct interaction between Mdm2 and Nbs1 and independent of p53. Regardless of p53 status, increased levels of Mdm2, but not Mdm2 lacking its Nbs1-binding domain, caused delays in DNA break repair, chromosomal abnormalities, and genome instability. These data demonstrated Mdm2-induced genome instability can be mediated through Mdm2:Nbs1 interactions and independent from its association with p53.

References

  1. ↑ "Amplification of a gene encoding a p53-associated protein in human sarcomas". Nature 358 (6381): 80–3. July 1992. doi:10.1038/358080a0. PMID 1614537. Bibcode: 1992Natur.358...80O. 
  2. ↑ "Hdmx modulates the outcome of p53 activation in human tumor cells". The Journal of Biological Chemistry 281 (44): 33036–44. November 2006. doi:10.1074/jbc.M605405200. PMID 16905769. 
  3. ↑ "MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53". Molecular Cell 61 (1): 68–83. January 2016. doi:10.1016/j.molcel.2015.12.008. PMID 26748827. 
  4. ↑ "MDM2 beyond cancer: podoptosis, development, inflammation, and tissue regeneration". Histology and Histopathology 30 (11): 1271–82. November 2015. doi:10.14670/HH-11-636. PMID 26062755. 
  5. ↑ "The Functional Roles of the MDM2 Splice Variants P2-MDM2-10 and MDM2-∆5 in Breast Cancer Cells". Translational Oncology 10 (5): 806–817. October 2017. doi:10.1016/j.tranon.2017.07.006. PMID 28844019. 
  6. ↑ "In vivo activation of the p53 pathway by small-molecule antagonists of MDM2". Science 303 (5659): 844–8. February 2004. doi:10.1126/science.1092472. PMID 14704432. Bibcode: 2004Sci...303..844V. 
  7. ↑ "Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation". The EMBO Journal 21 (14): 3715–27. July 2002. doi:10.1093/emboj/cdf384. PMID 12110584. 
  8. ↑ 8.0 8.1 "Subcellular localization of beta-arrestins is determined by their intact N domain and the nuclear export signal at the C terminus". The Journal of Biological Chemistry 278 (13): 11648–53. March 2003. doi:10.1074/jbc.M208109200. PMID 12538596. 
  9. ↑ 9.0 9.1 "Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor". The Journal of Biological Chemistry 283 (32): 22166–76. August 2008. doi:10.1074/jbc.M709668200. PMID 18544533. 
  10. ↑ "Beta-arrestin 2 functions as a G-protein-coupled receptor-activated regulator of oncoprotein Mdm2". The Journal of Biological Chemistry 278 (8): 6363–70. February 2003. doi:10.1074/jbc.M210350200. PMID 12488444. 
  11. ↑ "Cyclin G1 has growth inhibitory activity linked to the ARF-Mdm2-p53 and pRb tumor suppressor pathways". Molecular Cancer Research 1 (3): 195–206. January 2003. PMID 12556559. 
  12. ↑ 12.0 12.1 "Hdm2 recruits a hypoxia-sensitive corepressor to negatively regulate p53-dependent transcription". Current Biology 13 (14): 1234–9. July 2003. doi:10.1016/S0960-9822(03)00454-8. PMID 12867035. https://eprints.soton.ac.uk/26486/1/AHM2003_postprint.pdf. 
  13. ↑ 13.0 13.1 13.2 "p14ARF interacts with DAXX: effects on HDM2 and p53". Cell Cycle 7 (12): 1836–50. June 2008. doi:10.4161/cc.7.12.6025. PMID 18583933. 
  14. ↑ "MDM2 regulates dihydrofolate reductase activity through monoubiquitination". Cancer Research 68 (9): 3232–42. May 2008. doi:10.1158/0008-5472.CAN-07-5271. PMID 18451149. 
  15. ↑ "p300/MDM2 complexes participate in MDM2-mediated p53 degradation". Molecular Cell 2 (4): 405–15. October 1998. doi:10.1016/S1097-2765(00)80140-9. PMID 9809062. 
  16. ↑ "A comprehensive resource of interacting protein regions for refining human transcription factor networks". PLOS ONE 5 (2): e9289. Feb 2010. doi:10.1371/journal.pone.0009289. PMID 20195357. Bibcode: 2010PLoSO...5.9289M. 
  17. ↑ "FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53". FEBS Letters 583 (4): 621–6. February 2009. doi:10.1016/j.febslet.2009.01.009. PMID 19166840. 
  18. ↑ "Mdm2 induces mono-ubiquitination of FOXO4". PLOS ONE 3 (7): e2819. 2008. doi:10.1371/journal.pone.0002819. PMID 18665269. Bibcode: 2008PLoSO...3.2819B. 
  19. ↑ 19.0 19.1 19.2 "Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2". Molecular and Cellular Biology 28 (13): 4365–76. July 2008. doi:10.1128/MCB.01662-07. PMID 18426907. 
  20. ↑ "MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation". The EMBO Journal 21 (22): 6236–45. November 2002. doi:10.1093/emboj/cdf616. PMID 12426395. 
  21. ↑ "Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function". The Journal of Biological Chemistry 278 (16): 13595–8. April 2003. doi:10.1074/jbc.C200694200. PMID 12606552. 
  22. ↑ "Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha". Genes & Development 14 (1): 34–44. January 2000. doi:10.1101/gad.14.1.34. PMID 10640274. 
  23. ↑ "Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation". The EMBO Journal 21 (7): 1704–12. April 2002. doi:10.1093/emboj/21.7.1704. PMID 11927554. 
  24. ↑ "Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis". Cancer Research 68 (14): 5669–77. July 2008. doi:10.1158/0008-5472.CAN-07-6364. PMID 18632619. 
  25. ↑ "MdmX inhibits Smad transactivation". Oncogene 21 (57): 8776–85. December 2002. doi:10.1038/sj.onc.1205993. PMID 12483531. 
  26. ↑ "MDM2 interacts with MDMX through their RING finger domains". FEBS Letters 447 (1): 5–9. March 1999. doi:10.1016/S0014-5793(99)00254-9. PMID 10218570. 
  27. ↑ "MdmX is a RING finger ubiquitin ligase capable of synergistically enhancing Mdm2 ubiquitination". The Journal of Biological Chemistry 277 (51): 49668–75. December 2002. doi:10.1074/jbc.M208593200. PMID 12393902. 
  28. ↑ "Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans". Cell Death and Differentiation 15 (5): 841–8. May 2008. doi:10.1038/sj.cdd.4402309. PMID 18219319. 
  29. ↑ "Mammalian Numb is a target protein of Mdm2, ubiquitin ligase". Biochemical and Biophysical Research Communications 302 (4): 869–72. March 2003. doi:10.1016/S0006-291X(03)00282-1. PMID 12646252. 
  30. ↑ "NUMB controls p53 tumour suppressor activity". Nature 451 (7174): 76–80. January 2008. doi:10.1038/nature06412. PMID 18172499. Bibcode: 2008Natur.451...76C. 
  31. ↑ 31.0 31.1 31.2 "Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway". Molecular and Cellular Biology 23 (23): 8902–12. December 2003. doi:10.1128/MCB.23.23.8902-8912.2003. PMID 14612427. 
  32. ↑ "ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways". Cell 92 (6): 725–34. March 1998. doi:10.1016/S0092-8674(00)81401-4. PMID 9529249. 
  33. ↑ "Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2". Oncogene 21 (29): 4498–507. July 2002. doi:10.1038/sj.onc.1205558. PMID 12085228. 
  34. ↑ "The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53". Cell 92 (6): 713–23. March 1998. doi:10.1016/S0092-8674(00)81400-2. PMID 9529248. 
  35. ↑ "Mdm2 promotes the rapid degradation of p53". Nature 387 (6630): 296–9. May 1997. doi:10.1038/387296a0. PMID 9153395. Bibcode: 1997Natur.387..296H. 
  36. ↑ "Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53". FEBS Letters 420 (1): 25–7. December 1997. doi:10.1016/S0014-5793(97)01480-4. PMID 9450543. 
  37. ↑ "Mdm2 binds p73 alpha without targeting degradation". Oncogene 18 (27): 3923–9. July 1999. doi:10.1038/sj.onc.1202781. PMID 10435614. 
  38. ↑ "MDM2 suppresses p73 function without promoting p73 degradation". Molecular and Cellular Biology 19 (5): 3257–66. May 1999. doi:10.1128/mcb.19.5.3257. PMID 10207051. 
  39. ↑ "MDM2 inhibits PCAF (p300/CREB-binding protein-associated factor)-mediated p53 acetylation". The Journal of Biological Chemistry 277 (34): 30838–43. August 2002. doi:10.1074/jbc.M204078200. PMID 12068014. 
  40. ↑ "Retinoblastoma protein modulates gankyrin-MDM2 in regulation of p53 stability and chemosensitivity in cancer cells". Oncogene 27 (29): 4034–43. July 2008. doi:10.1038/onc.2008.43. PMID 18332869. 
  41. ↑ "Proteasome activator PA28 gamma regulates p53 by enhancing its MDM2-mediated degradation". The EMBO Journal 27 (6): 852–64. March 2008. doi:10.1038/emboj.2008.25. PMID 18309296. 
  42. ↑ "The ribosomal L5 protein is associated with mdm-2 and mdm-2-p53 complexes". Molecular and Cellular Biology 14 (11): 7414–20. November 1994. doi:10.1128/mcb.14.11.7414. PMID 7935455. 
  43. ↑ "PML regulates p53 stability by sequestering Mdm2 to the nucleolus". Nature Cell Biology 6 (7): 665–72. July 2004. doi:10.1038/ncb1147. PMID 15195100. 
  44. ↑ "MDM2 and promyelocytic leukemia antagonize each other through their direct interaction with p53". The Journal of Biological Chemistry 278 (49): 49286–92. December 2003. doi:10.1074/jbc.M308302200. PMID 14507915. 
  45. ↑ "Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization". Journal of Cell Science 116 (Pt 19): 3917–25. October 2003. doi:10.1242/jcs.00714. PMID 12915590. 
  46. ↑ "Physical and functional interactions between PML and MDM2". The Journal of Biological Chemistry 278 (31): 29288–97. August 2003. doi:10.1074/jbc.M212215200. PMID 12759344. 
  47. ↑ "Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26". Molecular Cell 32 (2): 180–9. October 2008. doi:10.1016/j.molcel.2008.08.031. PMID 18951086. 
  48. ↑ "ATM-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53R2 protein against MDM2 to DNA damage". Proceedings of the National Academy of Sciences of the United States of America 105 (47): 18519–24. November 2008. doi:10.1073/pnas.0803313105. PMID 19015526. Bibcode: 2008PNAS..10518519C. 
  49. ↑ "RYBP stabilizes p53 by modulating MDM2". EMBO Reports 10 (2): 166–72. February 2009. doi:10.1038/embor.2008.231. PMID 19098711. 
  50. ↑ "The MDM2 C-terminal region binds to TAFII250 and is required for MDM2 regulation of the cyclin A promoter". The Journal of Biological Chemistry 272 (49): 30651–61. December 1997. doi:10.1074/jbc.272.49.30651. PMID 9388200. 
  51. ↑ "Repression of p53-mediated transcription by MDM2: a dual mechanism". Genes & Development 11 (15): 1974–86. August 1997. doi:10.1101/gad.11.15.1974. PMID 9271120. 
  52. ↑ "The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex". The EMBO Journal 27 (13): 1863–74. July 2008. doi:10.1038/emboj.2008.115. PMID 18566590. 
  53. ↑ "CARPs enhance p53 turnover by degrading 14-3-3sigma and stabilizing MDM2". Cell Cycle 7 (5): 670–82. March 2008. doi:10.4161/cc.7.5.5701. PMID 18382127. 

Further reading

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