MDM2

AGCOH

Definition: MDM2 is an oncoprotein best characterized for its role in the inactivation and degradation of the p53 tumor suppressor. However, MDM2 has many other binding partners and its p53-independent role in the regulation of cell growth and survival appears to be extremely complex. The MDM2 is an ubiquitin-protein ligase that promotes p53 protein degradation (TP53).

MDM2 acts as a major regulator of the tumor suppressor p53 (MIM.191170) by targeting its destruction. p14ARF increases p53 levels by inhibiting MDM2 activity.

The gene encompasses 33 kb of DNA and have 12 exons. The MDM2 gene codes for 2.3 kb nucleotides mRNA with a 1476 bases open reading frame (ORF). MDM2 protein is found in nucleus and cytoplasm.

Images

 Pulmonary artery intimal sarcoma with MDM2 amplification
https://twitter.com/AnneMillsMD/status/827558368923549696

Functions

MDM2 acts as an ubiquitin ligase promoting proteasome dependent degradation of p53. MDM2 is also a transcriptional target of p53 such that p53 activity controls the expression and protein level of its own negative regulator, providing for an elegant feedback loop.

MDM2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. The MDM2-p53 complex also inhibits p53 mediated transactivation.

MDM2 involves nuclear export of p53 protein.

Interaction between the p53 and MDM2 is not sufficient to mediate p53 degradation. The p53­MDM2 complex must be shuttled from the nucleus to the cytoplasm in order for p53 degradation.

Besides, the MDM2 protein also promotes RB (retinoblastoma) protein degradation in a proteasome-dependent manner in human tumor cell lines. MDM2 overexpression contributes to cancer development in part by destabilizing RB. (16337594)

Interaction between MDM2 and the tumor suppressor genes p53 and Rb lead to deregulate cell proliferation and apoptosis.

Both MDM2 and Pirh2 (RCHY1) proteins are p53 ubiquitin-protein E3 ligases promoting for degradation of p53 protein. However, MDM2 operates in a distinct manner from Pirh2 in response to DNA damage in cancer cells. MDM2 protein is reduced or absent in the p53 null cells compared to the p53 positive cells, Whereas, Pirh2 expression is not affected by the status of p53.

 MDM2 displays differential activities dependent upon the activation status of NFkappaB. (17938575)

Pathology

MDM2 is a key factor in human tumorigenesis. MDM2 is amplified in many cancers.

The increased MDM2 protein could play an important role in tumorigenesis, especially in the development of soft tissue tumors, osteosarcomas and esophageal carcinomas.

The overall frequency of MDM2 amplification in human tumors is 7%. Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%).

 MDM2 amplification and overexpression in tumors

• lymphomas (9172803)
• leukemias (8219216, 9172803)
• esophageal carcinomas (13%)
• low-grade osteosarcomas (16 to 30%) (30001240)
• soft tissue tumors (20%)
  • liposarcomas (16160477), as atypical lipomatous tumor/well-differentiated liposarcoma (ALT-WDLPS) (16160477) or dedifferentiated liposarcoma (DDLPS) (16160477)
  • leiomyosarcoma (15024701)
  • alveolar rhabdomyosarcoma (ARMS) (15024701, 11742497)
  • embryonal rhabdomyosarcoma (ERMS) (15024701, 11742497)

• melanomas (16419059)

MDM2 gene is overexpressed in some types of leukemias and lymphomas. Overexpression was significantly more frequent in the low-grade type of B-cell non-Hodgkin’s lymphoma (B-NHL) than in the intermediate/high grade types of lymphoma and the overexpression was also significantly more frequent in the advanced rather than the earlier stages of B-cell chronic lymphocytic leukemia (B-CLL).

MDM2 is amplified in approximately 30% of osteosarcomas and soft tissue tumors.

A single nucleotide polymorphism (SNP309) found in the MDM2 promoter is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. (15550242)

MDM2 mutations are uncommon. Point mutations were reported in human cancers.

Mouse models

MDM2 was originally cloned from transformed Balb/c3T3 cell line called 3T3DM and was identified as an amplified oncogene in murine cell lines.

Expression of MDM2 during embryogenesis was studied in mice. During 14.5 to 18.5 days of prenatal development, the nasal respiratory epithelium expresses high levels of MDM2 RNA and protein in both wild type and p53 null embryos. MDM2 expression during development is tissue-specific and is independent of p53. The mdm2 basal mRNA expression appears relatively moderate in most organs in adult mice.

MDM2 knockout mouse embryos died during development and deletion of the p53 gene rescues MDM2 null embryos. These studies suggested that p53 is lethal in the absence of MDM2 during mouse development and MDM2 is a critical regulator to control p53 activity.

Diagnostic pathology

 Detection of MDM2 gene amplification or protein expression distinguishes sclerosing mesenteritis and retroperitoneal fibrosis from inflammatory well-differentiated liposarcoma (WDLS) (18836421)

Homology

The MDM2 gene has been identified in various organisms including mammals, amphibians and fishes. It belongs to the ring finger ubiquitin protein E3 ligase family, containing Conserved RING-finger Domain.

Antagonists

 Nutlin-3A (17354236)

Immunochemistry

 The combination of MDM2 or CDK4 shows 100% sensitivity and 97.5% specificity for the diagnosis of low-grade osteosarcoma (as rarosteal osteosarcoma and low-grade central osteosarcoma). (20601938)

• MDM2 and CDK4 immunostains therefore reliably distinguish low-grade osteosarcoma from benign histological mimics.
• The MDM2/CDK4 combination may serve as a useful adjunct in this difficult differential diagnosis. (20601938)
• Low-grade osteosarcoma is often confused with benign lesions.

Pathology

 MDM2 amplification

• Pulmonary artery intimal sarcoma with MDM2 amplification
• https://twitter.com/AnneMillsMD/status/827558368923549696

Open references

 MDM2 and MDMX: Alone and together in regulation of p53. Shadfan M, Lopez-Pajares V, Yuan ZM. Transl Cancer Res. 2012 Aug;1(2):88-89. PMID: 23002429 [Free]

Reviews

 Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med. 2007 Jan;13(1):23-31. PMID: 17126603

 Harris LC. MDM2 splice variants and their therapeutic implications. Curr Cancer Drug Targets. 2005 Feb;5(1):21-6. PMID: 15720186

 Chene P. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer. 2003 Feb;3(2):102-9. PMID: 12563309

 Daujat S, Neel H, Piette J. MDM2: life without p53. Trends Genet. 2001 Aug;17(8):459-64. PMID: 11485818

Paywall References

 Consistent Amplification of FRS2 and MDM2 in Low-grade Osteosarcoma: A Genetic Study of 22 Cases With Clinicopathologic Analysis. He X, Pang Z, Zhang X, Lan T, Chen H, Chen M, Yang H, Huang J, Chen Y, Zhang Z, Jing W, Peng R, Zhang H. Am J Surg Pathol. 2018 Jul 11. doi : 10.1097/PAS.0000000000001125 PMID: 30001240

 Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor. Kashima T, Halai D, Ye H, Hing SN, Delaney D, Pollock R, O’Donnell P, Tirabosco R, Flanagan AM. Mod Pathol. 2012 Jun 15. PMID: 22699518

 Immunohistochemical analysis of MDM2 and CDK4 distinguishes low-grade osteosarcoma from benign mimics. Yoshida A, Ushiku T, Motoi T, Shibata T, Beppu Y, Fukayama M, Tsuda H. Mod Pathol. 2010 Jul 2. PMID: 20601938

 Immunohistochemical analysis of MDM2 and CDK4 distinguishes low-grade osteosarcoma from benign mimics. Yoshida A, Ushiku T, Motoi T, Shibata T, Beppu Y, Fukayama M, Tsuda H. Mod Pathol. 2010 Jul 2. PMID: 20601938

 Weaver J, Goldblum JR, Turner S, Tubbs RR, Wang WL, Lazar AJ, Rubin BP. Detection of MDM2 gene amplification or protein expression distinguishes sclerosing mesenteritis and retroperitoneal fibrosis from inflammatory well-differentiated liposarcoma. Mod Pathol. 2008 Oct 3. PMID: 18836421

 Sirvent N, Coindre JM, Maire G, Hostein I, Keslair F, Guillou L, Ranchere-Vince D, Terrier P, Pedeutour F. Detection of MDM2-CDK4 Amplification by Fluorescence In Situ Hybridization in 200 Paraffin-embedded Tumor Samples: Utility in Diagnosing Adipocytic Lesions and Comparison With Immunohistochemistry and Real-time PCR. Am J Surg Pathol. 2007 Oct;31(10):1476-1489. PMID: 17895748

 Müller CR, Paulsen EB, Noordhuis P, Pedeutour F, Saeter G, Myklebost O. Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A. Int J Cancer. 2007 Jul 1;121(1):199-205. PMID: 17354236

 Shimada S, Ishizawa T, Ishizawa K, Matsumura T, Hasegawa T, Hirose T. The value of MDM2 and CDK4 amplification levels using real-time polymerase chain reaction for the differential diagnosis of liposarcomas and their histologic mimickers. Hum Pathol. 2006 Sep;37(9):1123-9. PMID: 16938516

 Muthusamy V, Hobbs C, Nogueira C, Cordon-Cardo C, McKee PH, Chin L, Bosenberg MW. Amplification of CDK4 and MDM2 in malignant melanoma. Genes Chromosomes Cancer. 2006 May;45(5):447-54. PMID: 16419059

 Binh MB, Sastre-Garau X, Guillou L, Pinieux GD, Terrier P, Lagace R, Aurias A, Hostein I, Coindre JM. MDM2 and CDK4 Immunostainings Are Useful Adjuncts in Diagnosing Well-Differentiated and Dedifferentiated Liposarcoma Subtypes: A Comparative Analysis of 559 Soft Tissue Neoplasms With Genetic Data. Am J Surg Pathol. 2005 Oct;29(10):1340-1347. PMID: 16160477

 Ragazzini P, Gamberi G, Pazzaglia L, Serra M, Magagnoli G, Ponticelli F, Ferrari C, Ghinelli C, Alberghini M, Bertoni F, Picci P, Benassi MS. Amplification of CDK4, MDM2, SAS and GLI genes in leiomyosarcoma, alveolar and embryonal rhabdomyosarcoma. Histol Histopathol. 2004 Apr;19(2):401-11. PMID: 15024701

 Guo CS, Degnin C, Fiddler TA, Stauffer D, Thayer MJ. Regulation of MyoD activity and muscle cell differentiation by MDM2, pRb, and Sp1. J Biol Chem. 2003 Jun 20;278(25):22615-22. PMID: 12702724

 The MDM2 gene amplification database. Momand J, Jung D, Wilczynski S, Niland J. Nucleic Acids Res. 1998; 26(15):3453-3459. PMID: 9671804