Regulation of Actinomycin D induced upregulation of Mdm2 in H1299 cells.

Mdm2 is a critical negative regulator of the p53 tumor suppressor and also has many p53-independent functions. Deregulation of Mdm2 is closely associated with tumorigenesis. However, how Mdm2 is regulated in response to various stresses is not well understood. In this study, we found that Mdm2 was stabilized and upregulated upon Actinomycin D (ActD) treatment in the p53-deficient H1299 cell line. This Mdm2 upregulation was not dependent on the ribosomal protein L11, an essential player in ribosomal stress-induced p53 activation, but did require a NEDDylation-dependent mechanism. We further demonstrated that the ActD-induced Mdm2 stabilization may be modulated by the cell growth signaling, and that knockdown of Mdm2 enhanced ActD-induced cell death in H1299 cells. These results suggested a role of Mdm2 in the ribosomal stress response in the p53 deficient cells, which could be exploited in therapeutic use for treating cancers harboring p53 mutations.