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Phosphorylation by COP9 Signalosome‐Associated CK2 Promotes Degradation of p27 during the G1 Cell Cycle Phase
Author(s) -
Huang Xiaohua,
Wagner Erika,
Dumdey Renate,
Peth Andreas,
Berse Matthias,
Dubiel Wolfgang,
Berndt Christoph
Publication year - 2006
Publication title -
israel journal of chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.908
H-Index - 54
eISSN - 1869-5868
pISSN - 0021-2148
DOI - 10.1560/9219-25wn-yu1k-gdvv
Subject(s) - cop9 signalosome , ubiquitin ligase , chemistry , protein kinase b , phosphorylation , microbiology and biotechnology , proteasome , proteolysis , cell cycle , ubiquitin , kinase , protein kinase a , cyclin dependent kinase 2 , protein degradation , biochemistry , cell , biology , peptide hydrolases , gene , protease , enzyme
The cell cycle regulator p27 Kip1 (p27) is controlled by 26S proteasome‐mediated proteolysis by two different pathways. From the S till the G2 phase of the cell cycle, degradation of p27 takes place in the nucleus and is initiated by CDK2‐dependent phosphorylation of threonine 187 with subsequent ubiquitination by the SCF Skp2 ubiquitin ligase. During the G1 cell cycle phase (G1), p27 breakdown is cytosolic and is initiated by nuclear export with subsequent ubiquitination by a RING finger ligase called kip1 ubiquitination complex. Here we show that the COP9 signalosome (CSN) is a regulator of p27 proteolysis during G1. The CSN interacts with p27 and the CSN‐associated kinase CK2 phosphorylates p27 at two regions. One is central to the protein (amino acids 101–113), and the other was mapped near to the C‐terminus (amino acids 170–189). Elimination of the putative C‐terminal phosphorylation sites stabilizes ectopic p27 towards proteasomal degradation and abolishes CSN–p27 binding. Inhibition of CSN‐associated kinase activity by curcumin attenuates loss of p27 upon cell cycle re‐entry. Similar but not additive effects of the phosphoinositol‐3‐kinase blocker LY 290042 may point to a common pathway of CSN‐associated CK2 and protein kinase B/Akt (Akt) in regulating p27 abundance. Akt is found in Flag pulldowns of lysates obtained from cells permanently expressing Flag‐tagged CSN2, indicating that Akt is a novel kinase associated with the CSN. Thus, the CSN seems to regulate p27 proteolysis at G1 downstream of Ras‐mediated signal pathways.