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The MDM2-TP53 pathway

Watch a video to learn about the MDM2-TP53 pathway and its role in apoptosis and cell-cycle arrest.

The MDM2-TP53 pathway: A tumor-suppressor pathway that is often disrupted in cancer1

What is p53?

Aberrant murine double minute 2 (MDM2) expression restricts tumor protein p53 (TP53) and its tumor-suppressor functions, leaving cells more susceptible to oncogenic mutations and transformation.2-4

TP53: Guardian of the genome

MDM2 image: TP53: Guardian of the genome

To protect against harmful mutations that may cause cancer, human cells have evolved robust mechanisms to help maintain the integrity of the genome. The TP53 protein, which is classified as a tumor-suppressor gene, plays a unique role in conserving stability by preventing genome mutation. As the cellular gatekeeper, the TP53 tumor suppressor gene coordinates protective cellular responses to oncogenic stressors, such as hypoxia or DNA damage.5-7 By binding to specific DNA sequences, TP53 promotes transcription of various target genes that help initiate cell-cycle arrest, DNA damage repair, and apoptosis, among other tumor-suppressive processes.8-13

MDM2: Negative regulator of TP53

MDM2 image: MDM2: Negative regulator of TP53

TP53 activity is tightly controlled by MDM2, its primary negative regulator. In the absence of stress, the MDM2 protein binds to the transactivation domain of TP53, preventing it from binding to DNA and marking it for proteasomal degradation. In this way, MDM2-TP53 interaction limits TP53 abundance and TP53-mediated tumor-suppressor functions.2-4,8,14-17

Aberrant MDM2 restricts TP53-mediated tumor suppression

MDM2 image: Aberrant MDM2 restricts TP53-mediated tumor suppression

MDM2 drives TP53 dysfunction in many cancers. A number of hematologic cancers, including acute myeloid leukemia (AML) and some solid tumors, have TP53 dysfunction due to abnormal activity of certain TP53 regulatory proteins. MDM2 is one such important regulatory protein.18-20 Mutations that result in aberrant expression of MDM2 can lead to a loss of the tumor-suppressor function of TP53, leaving normal cells more susceptible to oncogenic mutations, transformation, and subsequent tumor growth.2-4 Preclinical data have shown that blocking MDM2 interactions with TP53 may induce apoptosis in both MDM2-overexpressing and wild-type tumor cell lines.18,21

References

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