Dual mode of regulation of cell division cycle 25 A protein by TRB3.
We have recently demonstrated that TRB3, a novel stress-inducible protein, is an unstable protein regulated by the ubiquitin-proteasome system. The expression level of TRB3 protein is down-regulated by anaphase-promoting complex/cyclosome-cell division cycle division 20 homolog 1 (APC/C(Cdh1)) through its D-box motif. Here we demonstrate that TRB3 regulates the stability of cell division cycle 25 A (Cdc25A), an essential activator of cyclin dependent kinases (CDKs). The expression level of Cdc25A protein is suppressed by over-expression of TRB3, while knockdown of TRB3 enhances the endogenous Cdc25A expression level. On the other hand, Cdc25A degradation induced by DNA damage is significantly rescued by TRB3. When serine residues in the DSG motif, which is the critical sequences for the degradation of Cdc25A induced by DNA damage, is mutated to alanine (Cdc25A(DSG2X)), both stimulatory and protective effects of TRB3 on the Cdc25A degradation is disappeared. TRB3 protein interacts with both wild Cdc25A and mutant Cdc25A(DSG2X). Expression level of the endogenous TRB3 protein is down-regulated in a genotoxic condition. These results suggest TRB3 is a regulator for adjusting the expression level of Cdc25A both in a normal and a genotoxic conditions.
Sakai
Satoshi
S
Department of Drug Metabolism and Disposition, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
Ohoka
Nobumichi
N
Onozaki
Kikuo
K
Kitagawa
Masatoshi
M
Nakanishi
Makoto
M
Hayashi
Hidetoshi
H
D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D004249:DNA Damage; D006801:Humans; D047468:Immunoprecipitation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology* / Q000037:antagonists & inhibitors; D034622:RNA Interference; D012097:Repressor Proteins / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000502:physiology*
D018797:Cell Cycle Proteins; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D017346:Protein Serine-Threonine Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases