The ubiquitin ligase COP1 is a critical negative regulator of p53

Abstract

COP1 (constitutively photomorphogenic 1) is a RING-finger-containing protein that functions to repress plant photomorphogenesis, the light-mediated programme of plant development. Mutants of COP1 are constitutively photomorphogenic, and this has been attributed to their inability to negatively regulate the proteins LAF1 (ref. 1) and HY5 (ref. 2). The role of COP1 in mammalian cells is less well characterized. Here we identify the tumour-suppressor protein p53 as a COP1-interacting protein. COP1 increases p53 turnover by targeting it for degradation by the proteasome in a ubiquitin-dependent fashion, independently of MDM2 or Pirh2, which are known to interact with and negatively regulate p53. Moreover, COP1 serves as an E3 ubiquitin ligase for p53 in vitro and in vivo, and inhibits p53-dependent transcription and apoptosis. Depletion of COP1 by short interfering RNA (siRNA) stabilizes p53 and arrests cells in the G1 phase of the cell cycle. Furthermore, we identify COP1 as a p53-inducible gene, and show that the depletion of COP1 and MDM2 by siRNA cooperatively sensitizes U2-OS cells to ionizing-radiation-induced cell death. Overall, these results indicate that COP1 is a critical negative regulator of p53 and represents a new pathway for maintaining p53 at low levels in unstressed cells.

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4

“…A number of other p53 ubiquitin ligases, such as Pirh2, Cop-1, Yin Yang1 and ARF/BP1, have indeed been discovered and shown to function in a Mdm2-independent manner. [22][23][24][25] Together these data challenge the conventional view that Mdm2 is essential for p53 turnover in vivo. A clear answer to this key issue could have come from studies of the mdm2-deletion mutants.…”

The P53 pathway: what questions remain to be explored?

“…Recently, two other ubiquitin ligases were shown to act upon the p53 protein, COP-1 and PIRH-2. 19,20 Why is this redundancy employed? What are the roles of these enzymes for the many diverse stress inputs, in different tissue or cell types or at the different times in development of an organism?…”

Some p53-binding proteins that can function as arbiters of life and death

“…65 It will be interesting to determine whether Pin1 activity can also affect the pathways, yet elusive, which engage the p53 DNA-binding domain with the ubiquitin ligases Pirh2 and COP1. 66,67 p53 transcriptional activity is also regulated by interaction with acetyltransferases and stress-activated isomerization of p53 stimulates the acetylation of p53 C-terminal lysine residues by p300/CBP (G Del Sal, unpublished data), analogous to p73. 68 Furthermore, these events have been linked to the induction of proapoptotic target genes.…”