| dc.description.abstract | p27 is a critical CDK inhibitor involved in cell cycle regulation, but its response to
DNA damage remains unclear. Constitutive photomorphogenesis 1 (COP1), a p53-
targeting E3 ubiquitin ligase, is downregulated by DNA damage, but the biological
consequences of this phenomenon are poorly understood. Here, we report that p27
levels were elevated after DNA damage, with concurrent reduction of COP1 levels.
Mechanistic studies showed that COP1 directly interacted with p27 through a VP motif
on p27 and functions as an E3 ligase of p27 to accelerate the ubiquitin-mediated
degradation of p27. Also, COP1 overexpression lead to cytoplasmic distribution of p27,
thereby accelerating p27 degradation. COP1 overexpression resulted in elevation of
Aurora A kinase. COP1 and Aurora A levels were positively correlated in patient
samples and associated with poor overall survival. We found that COP1 expression
promoted cell proliferation, cell transformation, and tumor progression, manifesting its
role in cancer promotion whereas p27 negatively regulated COP1 function and
prevented tumor growth in a mouse xenograft model of human cancer. Together, these
findings define a mechanism for posttranslational regulation of p27 after DNA damage
that can explain the correlation between COP1 overexpression and p27 downregulation
during tumorigenesis. | en |
