The MDM2-p53 pathway

The MDM2-p53 pathway is a tumor-suppressor pathway that is often disrupted in cancer.1

p53: a cellular gatekeeper

The transcription factor p53 is a tumor suppressor that is activated by cellular stress, such as low nutrients or DNA damage.6 Activation of the p53 pathway leads to normal processes that keep cell growth and cell proliferation in check, including apoptosis, cell-cycle arrest, senescence, and DNA repair.

Dysregulation of the p53 pathway is the most frequent alteration in a broad range of malignancies.2 p53 dysregulation can lead to replication of damaged cells, which can then acquire further genetic abnormalities and transform to a malignant phenotype.5

Although p53 is mutated in many cases, functional p53 can still be expressed and play a role in cell-cycle arrest and apoptosis.7

Image showing p53 apoptosis, cell-cycle arrest, and DNA repair Image showing p53 apoptosis, cell-cycle arrest, and DNA repair

MDM2: a regulator of p53

Murine double minute 2 (MDM2) tightly controls p53 through a negative feedback loop, influencing protein levels in the cell.7

MDM2 controls p53 via 2 mechanisms7

  • Binding to p53 at its transactivation domain and blocking its ability to act as a transcription factor5
  • Serving as a specific E3 ubiquitin ligase for p53, facilitating proteasomal degradation and reducing levels of cellular p53
Image showing how p53 induces transcription of MDM2 and then acts to degrade p53 protein Image showing how p53 induces transcription of MDM2 and then acts to degrade p53 protein

1 p53 activates MDM2 transcription by binding to response elements in the MDM2 promoter region.7

2 Rising cellular levels of MDM2 bind to p53 at its transactivation domain and block its ability to act as a transcription factor.7

3 MDM2 also serves as a specific E3 ubiquitan ligase for p53.7

4 This facilitates proteasomal degradation and reduces the levels of p53, deactivating MDM2 response.7

MDM2 drives p53 dysfunction in many cancers

A number of hematologic cancers, including acute myeloid leukemia (AML) and some solid tumors, have p53 dysfunction due to abnormal activity of certain p53 regulatory proteins.2-4 MDM2 is one such important regulatory protein.

The central role of MDM2 in regulating p53 activity suggests that targeting the MDM2-p53 interaction itself could have an impact on the natural course of disease progression.2,7 Preclinical data have shown that blocking MDM2 interactions with p53 may induce apoptosis in both MDM2-overexpressing and wild-type tumor cell lines.2,7

Genentech and Roche are currently researching the MDM2 pathway.

References

  1. Nag S, Qin J, Srivenugopal KS, Wang M, Zhang R. The MDM2-p53 pathway revisited. J Biomed Res. 2013;27:254-271. PMID: 23885265
  2. Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med. 2007;13:23-31. PMID: 17126603
  3. Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26:3453-3459. PMID: 9671804
  4. Tan BX, Khoo KH, Lim TM, Lane DP. High Mdm4 levels suppress p53 activity and enhance its half-life in acute myeloid leukemia. Oncotarget. 2013;5:933-943. PMID: 24659749
  5. Melnikova VO, Ananthaswamy HN. P53 protein and non-melanoma skin cancer. In: Reichrath J, ed. Molecular Mechanisms of Basal Cell and Squamous Cell Carcinomas. Georgetown, TX: Landes Bioscience/Eurekah.com; 2005:66-72.
  6. Oren M. Decision making by p53: life, death, and cancer. Cell Death Differ. 2003;10:431-442. PMID: 12719720
  7. Vu BT, Vassilev LT. Small-molecule inhibitors of the p53-MDM2 interaction. Curr Top Microbiol Immunol. 2011;348:151-172. PMID: 21046355

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