MDM2
Description
The MDM2 (MDM2 proto-oncogene) is a protein-coding gene located on chromosome 12.
Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene. 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.
== Discovery and expression in tumor cells == The murine double minute (mdm2) oncogene, which codes for the Mdm2 protein, was originally cloned, along with two other genes (mdm1 and mdm3) from the transformed mouse cell line 3T3-DM. Mdm2 overexpression, in cooperation with oncogenic Ras, promotes transformation of primary rodent fibroblasts, and mdm2 expression led to tumor formation in nude mice. The human homologue of this protein was later identified and is sometimes called Hdm2. Further supporting the role of mdm2 as an oncogene, several human tumor types have been shown to have increased levels of Mdm2, including soft tissue sarcomas and osteosarcomas as well as breast tumors. An additional Mdm2 family member, Mdm4 (also called MdmX), has been discovered and is also an important negative regulator of p53.
== Ubiquitination target: p53 == The key target of Mdm2 is the p53 tumor suppressor. Mdm2 has been identified as a p53 interacting protein that represses p53 transcriptional activity. Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53.
MDM2 acts as an E3 ubiquitin ligase, tagging the tumor suppressor protein p53 for degradation by the proteasome. This prevents p53 from triggering cell cycle arrest and apoptosis, which are essential for preventing cancer growth. MDM2 also targets other proteins for degradation, including itself, ARRB1, retinoblastoma protein (RB1), DAXX, DYRK2, IGF1R, and SNAI1. It can also export p53 from the nucleus, further reducing its activity. MDM2 plays a complex role in regulating cellular processes, interacting with numerous proteins to fine-tune cellular responses to various stimuli, including DNA damage, growth factor signaling, and apoptosis. MDM2's interaction with NDUFS1 disrupts mitochondrial respiration, leading to oxidative stress and apoptosis. MDM2 is involved in regulating synaptic plasticity and dendritic spine density.
MDM2 is also known as ACTFS, HDMX, LSKB, hdm2.
