Constitutive Photomorphogenesis Protein 1 (COP1) and COP9 Signalosome, Evolutionarily Conserved Photomorphogenic Proteins As Possible Targets of Melatonin

The ubiquitin proteasome system has been proposed as a possible mechanism involved in the multiple actions of melatonin. COP1 (constitutive photomorphogenesis protein 1), a RING finger-type ubiquitin E3 ligase formerly identified in Arabidopsis, is a central switch for the transition from plant growth underground in darkness (etiolation) to growth under light exposure (photomorphogenesis). In darkness, COP1 binds to photomorphogenic transcription factors driving its degradation via the 26S proteasome; blue light, detected by cryptochromes, and red and far-red light detected by phytochromes, negatively regulate COP1. Homologues of plant COP1 containing all the structural features present in Arabidopsis as well as E3 ubiquitin ligase activity have been identified in mice and humans. Substrates for mammalian (m) COP1 include p53, AP-1 and c-Jun, p27(Kip1) , ETV1, MVP, 14-3-3σ, C/EBPα, MTA1, PEA3, ACC, TORC2 and FOXO1. This mCOP1 target suggests functions related to tumorigenesis, gluconeogenesis, and lipid metabolism. The role of mCOP1 in tumorigenesis (either as a tumor promoter or tumor suppressor), as well as in glucose metabolism (inhibition of gluconeogenesis) and lipid metabolism (inhibition of fatty acid synthesis), has been previously demonstrated. COP1, along with numerous other ubiquitin ligases, is regulated by the COP9 signalosome; this protein complex is associated with the oxidative stress sensor Keap1 and the deubiquitinase USP15. The objective of this review was to provide new information on the possible role of COP1 and COP9 as melatonin targets. The hypothesis is based on common functional aspects of melatonin and COP1 and COP9, including their dependence on light, regulation of the metabolism, and their control of tumor growth.