Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers

Abstract

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.

Aurora B kinase phosphorylates and instigates degradation of p53

“…For example, DNA damage will activate ataxia telangiectasia-mutated (26,27) or Chk (28) kinase to modify and/or strengthen the stability and activity of p53 for initiating DNA repair or causing apoptosis. However, during tumorigenesis, p53 is also a target of many oncogenic signals, such as Akt (29,30), MDM2 (31, 32), COP1 (33)(34)(35), or CSN6 (36), and these oncogenic signals will decrease the protein level of p53. Aurora B is a protein overexpressed in many types of cancer.…”

COP9 Signalosome Subunit Csn8 Is Involved in Maintaining Proper Duration of the G1 Phase

“…Germline ablation of mouse Csn2, Csn3, Csn5, Csn6, and Csn8 all leads to early embryonic arrest and death (3,4,7,30,46). Similarly, in Arabidopsis, complete loss-of-function mutation of each of the CSN subunits results in early seedling lethality (47,48).…”

Dynamic Regulation of the COP9 Signalosome in Response to DNA Damage

“…Indeed, accumulating evidence indicates a correlation between aberrant functioning of the CSN and multiple cancers, making it an attractive target for therapeutic intervention (19,20). Frequent overexpression of CSN subunits, especially the MPN proteins CSN5 and CSN6, in a variety of human cancers is correlated with cancer progression and poor survival (21)(22)(23)(24), while inhibition or knockdown of CSN5 was shown to suppress tumor growth in mice (21,25). Targeting CSN for cancer intervention, however, requires an in-depth understanding of the processes that regulate its mode of action.…”