In support of this, Mdm2 gene amplification occurs in approximately 7% of all human cancers without concomitant p53 mutation 19 20 21, indicating that Mdm2 gene amplification facilitates tumorigenesis by inhibiting p53-mediated tumor suppressive pathways. Mdm2 is considered an oncogene due to the ability of its product to inhibit p53 tumor suppressor function. Once activated, p53 induces expression of a large number of genes that involve in various cellular processes such as cell cycle progression and apoptosis induction. Under stress conditions, such as DNA damage, Mdm2 undergoes ataxia telangiectasia mutated (ATM)-mediated phosphorylation and subsequent degradation 18, thereby triggering p53 stabilization and activation. In addition to the trans-E3 ligase activity toward p53, Mdm2 also mediates its own degradation through a self-catalytic mechanism 16 17. The principle ubiquitin E3 ligase for p53 is Mdm2 11 12 13, the importance of which is underscored by the findings that Mdm2 deficiency-caused early embryonic lethality in mice can be completely rescued by the concomitant deletion of p53 14 15. In unstressed cells, p53 levels are low due to its rapid ubiquitination and proteasomal degradation. p53 is primarily regulated at the level of stability.

Increasing evidence also suggests an important role of p53 in the regulation of cell metabolism, autophagy, and ferroptosis 6 7 8 9 10.ĭue to the potent anti-proliferative effect of p53, it is not surprising that p53 function is strictly restrained in unstressed cells. The extensively characterized responses invoked by p53 include cell cycle arrest, apoptosis, and senescence.

As a tumor suppressor, p53 activates anti-proliferative processes in response to a wide range of cellular stresses including DNA damage and oncogene activation. Even in tumors with wild-type p53, the p53 pathway is often disrupted by either expression of oncoproteins or defective regulations upstream or downstream to p53 1 5. In the development of more than half of human tumors, p53 is frequently inactivated by oncogenic mutations. The tumor suppressor p53 plays a pivotal role in the protection against cancer 1 2 3 4.

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