Mdm2 Promotes Genetic Instability and Transformation Independent of p53

MDM2 regulates a novel form of incomplete neoplastic transformation of Theileria parva infected lymphocytes

“…It is known that the p53-dependent mechanism involves inhibition of p53 activity by MDM2, by direct-binding (Momand et al, 1992), shuttling p53 from the nucleus to the cytoplasm (Tao and Levine, 1999), and inducing ubiquitination and hence degradation by the ubiquitin-proteasome system (Haupt et al, 1997). Several lines of evidence support a role for p53-independent functions of MDM2 in tumor formation (Bouska et al, 2008;Ganguli and Wasylyk, 2003).…”

Genome Stability Requires p53

“…Binding of Mdm2 to Nbs1 delays DNA break repair in a p53-independent manner and results in increased chromosome and chromatid breaks and fusions. Data suggest that the early DNA-damage signal is delayed by increased levels of Mdm2, and that this results in DNA breaks remaining for longer periods of time in cells that overexpress Mdm2 (Alt et al 2005;Bouska et al 2008). Under conditions in which Mdm2 levels are elevated, there is an increase in chromosome and chromatid breaks and increased transformation potential in cells that lack functional p53 (Bouska et al 2008).…”

“…1) (Melo and Eischen 2012). We have determined that Mdm2 binds to Nbs1 of the MRN DNA repair complex (Alt et al 2005;Bouska et al 2008). The MRN complex responds to DNA breaks and signals to other proteins to facilitate break repair (Rein and Stracker 2014).…”

Mdm2-mediated ubiquitylation: p53 and beyond

“…121 Perhaps newly discovered interactions of Mdm2 with Nbs1 account for the genomic instability. 122 In the Em-myc model, tumors that harbor p53 mutations also have increased levels of Mdm2. 44 Interestingly, many other Mdm2-interacting proteins that have been identified play a key role in the control of cell proliferation, including Rb, E2F1 and Smads.…”