Molecular mechanism of CCDC106 regulating the p53-Mdm2/MdmX signal axis

Abstract The tumor suppressor p53 (p53) is regulated by murine double minute 2 (Mdm2) and its homologous MdmX in maintaining the p53 basal level. The overexpressed Mdm2/MdmX inhibit the cellular p53 activity, highly relevant to cancer occurrence. The coiled-coil domain-containing protein 106 (CCDC106) has been identified as a p53-interacting partner. However, its molecular mechanism is still elusive. Here we show that CCDC106 functions as a signaling regulator of the p53-Mdm2/MdmX axis mediated by cellular p53. We identified that CCDC106 directly interacts with the p53 transactivation domain by competing with Mdm2 and MdmX. The CCDC106 overexpression downregulates the cellular level of p53 and Mdm2/MdmX, and the decreased p53 reversibly downregulates the cellular level of CCDC106. Our work not only provides a molecular mechanism of CCDC106 regulating the cellular levels of p53 and Mdm2/MdmX, but also suggests that the CCDC106-p53 interaction as a novel target for cancer therapy.