Roles for negative cell regulator 14-3-3σ in control of MDM2 activities

The 14-3-3 sigma, upregulated by p53 in response to DNA damage, can have a positive-feedback impact driving p53 activities and is a human cancer epithelial marker downregulated in various tumors. However, the precise roles of 14-3-3 sigma during tumorigenesis are not well characterized. Here, we show that 14-3-3 sigma is a critical regulator of murine double minute oncogene (MDM2). 14-3-3 sigma interacts with MDM2 at the RING domain. The C-terminal region of 14-3-3 sigma binds to MDM2 very efficiently. Importantly, 14-3-3 sigma overexpression leads to destabilization of MDM2 through enhancing MDM2 self-ubiquitination and accelerating turnover rate. Conversely, loss of 14-3-3 sigma results in a significant increase in MDM2 protein. Moreover, live-cell images indicated that 14-3-3 sigma can affect the location of MDM2 from the nucleus to the cytoplasm, and that MDM2-mediated cytoplasmic localization of p53 can be reversed by the presence of 14-3-3 sigma. Significantly, we further showed that 14-3-3 sigma causes MDM2 downregulation, thereby stabilizing p53 and inhibiting tumor growth in animal tumors. Also, 14-3-3 sigma blocks MDM2-mediated retinoblastoma degradation and p53 NEDDylation. Our results provide evidence that 14-3-3 sigma is a pivotal MDM2 regulator involved in blocking a variety of activities of MDM2.