COP1D, an alternatively spliced constitutive photomorphogenic-1 (COP1) product, stabilizes UV stress-induced c-Jun through inhibition of full-length COP1.
COP1 is an evolutionarily conserved RING-finger ubiquitin ligase acting within a Cullin-RING ligase (CRL) complex that promotes polyubiquitination of c-Jun and p53. Stability of the above substrates is affected by post-translational changes priming the proteins for polyubiquitination and proteasome-dependent degradation. However, degradation of both substrates is controlled indirectly by signaling pathways affecting the E3 ligases involved in their polyubiquitination. Here, we report the identification of COP1D, a ubiquitously expressed splice variant of COP1 lacking a portion of a coiled-coil region involved in intermolecular associations. While being unable to associate with other components of the CRL complex, COP1D exerts a dominant-negative function over the full-length protein, due to its ability to heterodimerize with COP1 and sequester it from the enzymatically active complex. Ectopic expression of COP1D antagonizes the function of COP1, while its selective downregulation by RNA interference promotes more efficient degradation of c-Jun and p53 by the full-length protein. The COP1/COP1D mRNA ratio is modulated by UV stress and a decreased COP1/COP1D ratio correlates with elevated c-Jun, but not p53 protein levels in invasive ductal breast cancer. Thus, dynamic changes of the COP1/COP1D ratio provide an additional level of regulation of the half-life of the substrates of this E3 ligase under homeostatic or pathological conditions.
Savio
M G
MG
Unit of Leukocyte Biology, Vita-Salute San Raffaele University School of Medicine, DIBIT-Scientific Institute San Raffaele, Milano, Italy.
Rotondo
G
G
Maglie
S
S
Rossetti
G
G
Bender
J R
JR
Pardi
R
R
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D004795:Enzyme Stability / Q000528:radiation effects; D006367:HeLa Cells; D006262:Health; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D007527:Isoenzymes; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C471981:COP1 protein, human; D044767:Ubiquitin-Protein Ligases; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex