The mammalian constitutive photomorphogenesis 9 (COP9) signalosome (CSN), a 
protein complex involved in embryonic development, is implicated in cell cycle 
regulation and the DNA damage response. Its role in tumor development, however, 
remains unclear. Here, we have shown that the COP9 subunit 6 (CSN6) gene is 
amplified in human breast cancer specimens, and the CSN6 protein is upregulated 
in human breast and thyroid tumors. CSN6 expression positively correlated with 
expression of murine double minute 2 (MDM2), a potent negative regulator of the 
p53 tumor suppressor. Expression of CSN6 appeared to prevent MDM2 
autoubiquitination at lysine 364, resulting in stabilization of MDM2 and 
degradation of p53. Mice in which Csn6 was deleted died early in embryogenesis 
(E7.5). Embryos lacking both Csn6 and p53 survived to later in embryonic 
development (E10.5), which suggests that loss of p53 could partially rescue the 
effect of loss of Csn6. Mice heterozygous for Csn6 were sensitized to 
γ-irradiation-induced, p53-dependent apoptosis in both the thymus and the 
developing CNS. These mice were also less susceptible than wild-type mice to 
γ-irradiation-induced tumorigenesis. These results suggest that loss of CSN6 
enhances p53-mediated tumor suppression in vivo and that CSN6 plays an important 
role in regulating DNA damage-associated apoptosis and tumorigenesis through 
control of the MDM2-p53 signaling pathway.