How does MDM2 interact with p53?
The MDM2 protein is a negative regulator of p53. After binding to p53, it inhibits its transcriptional activity, favours its nuclear export and stimulates its degradation. The overexpression of MDM2 in various tumours inhibits p53, therefore favouring uncontrolled cell proliferation.
Is p53 stabilized by MDM2?
Although the ability of MDM2 to inhibit p53 is critical under non-stressed cell conditions, p53 must be allowed to respond under certain circumstances. In the event of cellular stress, when a p53 response is required to protect the cell, various mechanisms ensure that MDM2 stops its inhibition of p53.
Does MDM2 destroy p53?
The transient transfection experiment showed that MDM2 greatly reduced p53 protein level by inducing proteasome degradation of p53. In contrast, a MDM2 mutant, defective in p53 interaction, was not effective in the induction of p53 protein degradation.
What is the function of MDM2?
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.
What is the importance of MDM2 in cells?
MDM2 is a positive regulator of E2F-1, which plays an important role in cell cycle , and XIAP, an anti-apoptotic protein . Therefore, MDM2 is a key player in human cancers and an important cancer therapeutic target. The increased expression of MDM2 in human tumors is mainly caused by gene amplification.
What is the role of MDM2 protein in regulating the biochemical stability of p53 protein?
The crucial role of Mdm2 in regulating p53 activity is illustrated by the p53-dependent lethality of Mdm2-null mice during early embryogenesis. Mdm2−/− mice display peri-implantation lethality due to unregulated p53 activity, and crossing these mice with the p53-null allele completely rescues Mdm2-null mice (98,99).
What does the MDM2 gene do?
Abstract. The MDM2 protein encoded by the mouse double minute 2 (MDM2) gene is the primary negative regulatory factor of the p53 protein. MDM2 can ligate the p53 protein via its E3 ubiquitin ligase, and the ubiquitinated p53 can be transferred to the cytoplasm and degraded by proteasomes.
What is MDM2 amplification?
MDM2 amplification by FISH is designed to detect amplification of the MDM2 gene to aid in patient diagnosis of soft tissue and bone tumors. In soft tissue tumors, MDM2 amplification is a frequent and specific finding in well differentiated liposarcoma/atypical lipomatous tumor (ref.
Where is MDM2?
In humans, the MDM2 gene (also known as HDM2) is located on chromosome 12q14. 3-q15 and most frequently expresses a 491 amino acid residue protein. MDM2 is amplified at an overall frequency of 7% in human cancers and at a higher frequency within soft tissue sarcomas, osteosarcomas, and esophageal carcinomas (4, 5).
What regulates MDM2?
MDM2 is highly regulated at both mRNA and protein levels in cells. MDM2 is a transcriptional target of p53. p53 binds to p53 consensus DNA binding element in the first intron of MDM2 gene to transcriptionally induce the expression of MDM2, and forms an auto-regulatory negative feedback loop with MDM2 [30–32].