Modulation of p53 and p73 levels by cyclin G: implication of a negative feedback regulation.
Cyclin G is a transcriptional target gene of tumor suppressor p53. Recent studies present evidence that cyclin G may play a central role in the p53-Mdm2 autoregulated module, but the precise function of cyclin G remains elusive. Here, we show a negative effect of cyclin G on the stability of p53 and p73. Cyclin G expression resulted in a dramatic decrease of p53 protein levels in response to DNA damage and abrogated irradiation-mediated G1 arrest along with an increase of S phase in MCF7 cells containing wild-type p53. In p53-null Saos2 cells, cyclin G inhibited p73 induction in response to genotoxic stress and delayed the camptothecin-mediated cell cycle arrest. Cyclin G interacts with p53 as well as p73, and its binding to p53 or p73 presumably mediates downregulation of p53 and p73. We also found that cyclin G-mediated reduction of p53 but not of p73 is Mdm2-dependent. Moreover, inhibition of cyclin G by small interfering RNA (siRNA) caused the accumulation of p53 and p73 protein levels in response to DNA damage. Therefore, our results imply that cyclin G is transcriptionally activated by p53 or p73, and, in turn, cyclin G negatively regulates the stabilization of p53 family proteins through an unknown mechanism different from ubiquitination or transcriptional control.
Ohtsuka
Takao
T
Hematology and Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Ryu
Hoon
H
Minamishima
Yohji A
YA
Ryo
Akihide
A
Lee
Sam W
SW
D015152:Blotting, Northern; D015153:Blotting, Western; D002453:Cell Cycle; D002469:Cell Separation; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism
C534702:CCNG1 protein, human; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2