A Functional SNP in MDM2 Promoter Mediates E2F1 Affinity to Modulate Cyclin D1 and Tumor Cell Proliferation

Mouse double-minute 2 homologue (MDM2) is a key negative regulator of the tumor suppressor p53 that initiates cell cycle arrest and apoptosis upon cellular stresses (Chen et al., 2014; Song et al., 2014). MDM2 directly binds to and inhibits p53 pathway by regulating its location, stability and activity (Michael and Oren, 2003). The mice with reduced MDM2 expression showed increased apoptosis in both epithelial and lymphocytes cells (Mendrysa et al., 2003). In humans, MDM2 overexpression is associated with accelerated cancer progression in multiple cancers including glioblastomas, bladder cancer and breast cancer (Schiebe et al., 2000; Hori et al., 2002; Burton et al., 2002; Tuna et al., 2003; Hitzenbichler et al., 2013; Xiong et al., 2013). In a subset of tumors, overexpression of MDM2 can substitute for inactivating p53 by mutation (Oliner et al., 1992; Leach et al., 1993). Jone et al. reported that Mdm2-overexpressing mice developed spontaneous tumors in a lifetime (Jones et al., 1995). Antagonizing MDM2 to inactivate p53 pathway might offer a new therapeutic strategy for tumorgenesis (Vassilev, 2007; Shangary and Wang, 2009).