What type of protein is MDM2?

MDM2 is an E3 ubiquitin ligase whose expression is positively regulated by phosphoinositide-3 kinase (PI3K)-protein kinase B (PKB-Akt) signaling [56].

What is the function of MDM2 protein?

MDM2 functions as an E3 ubiquitin ligase to degrade p53. MDM2 also binds another tumor suppressor, ARF. This interaction sequesters MDM2 in the nucleolus away from p53, thus activating p53. Many additional MDM2 interacting proteins have been identified.

Is MDM2 a tumor suppressor gene or a proto-oncogene?

The mdm 2 gene is a cellular proto-oncogene that is often amplified in ∼7% of all human cancers, but is more frequently observed in soft-tissue sarcomas ( 77–79 ). Over-expression of MDM2 protein can also occur by increased transcription or enhanced translation ( 80 ).

What is p53 degradation?

The mechanism of p53 proteasomal degradation through polyubiquitination is well characterized. The basic assumption behind this mechanism is that p53 is inherently stable unless sensitized to degradation by polyubiquitination. However, a number of studies provide evidence for p53 to be naturally unstable.

What regulates MDM2?

Regulation of MDM2 Protein. MDM2 protein levels and activity are highly regulated by many extracellular and intracellular stress signals, including genotoxic stress signals, oncogenic activation, ribosomal stress, and psychological stress signals.

How do MDM2 inhibitors work?

MDM2 then inhibits the p53-mediated transcription of MDM2 and other downstream target genes by binding to p53, blocking its transactivation domain. Through E3 ubiquitin ligase activity, MDM2 promotes ubiquitination of p53, leading to increased p53 degradation.

Does MDM2 bind to p53?

MDM2 directly binds to the transactivation domain of p53 and inhibits its transcriptional activity, causes the ubiquitination and proteasomal degradation of p53, and exports p53 out of the nucleus which promotes p53 degradation and inhibits its activity.

How does p53 get degraded?

p53 is usually kept inactive due to ubiquitination by a number of E3 ubiquitin ligases that target p53 for proteasomal degradation. The ubiquitously expressed proto-oncogene Mdm2 is the major E3 ubiquitin ligase involved in this process and is critical for regulating p53 homeostasis.

How is p53 kept inactive?

p53 is maintained at low protein levels during times of homeostasis, when the cell is not exposed to stress or DNA-damaging events, by its predominant negative regulator Mdm2 through the ubiquitin-proteasome pathway.

What is the function of the Mdm2 protein?

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.

How does p53 regulate Mdm2 stability after DNA damage?

Regulation of MDM2 Stability After DNA Damage Cells in our body are constantly exposed to various stresses and threats to their genomic integrity. The tumor suppressor protein p53 plays a critical role in successful defense against these threats by inducing apoptotic cell death or cell cycle arrest. In unstressed conditions, p53 levels and acti …

What is Mdm2-mediated ubiquitination?

MDM2-mediated ubiquitination is enhanced by DNA damage. 195 The MDM2 gene, located at 12q14, is amplified in 10% to 15% of osteosarcomas. 168,174,175,196-198 Usually, MDM2 amplification occurs in tumors without p53 mutations, and thus MDM2 amplification acts as an alternative mechanism of p53 inactivation.

What is the function of USP7 and Mdm2?

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.