KAP1 dictates p53 response induced by chemotherapeutic agents via Mdm2 interaction.
KAP1 recruits many proteins involved in gene silencing and functions as an integral part of co-repressor complex. KAP1 was identified as Mdm2-binding protein and shown to form a complex with Mdm2 and p53 in vivo. We examined the role of KAP1 in p53 activation after the treatment of cells with different types of external stresses. KAP1 reduction markedly enhanced the induction of p21, a product of the p53 target gene, after treatment with actinomycin D or gamma-irradiation, but not with camptothecin. Treatment with actinomycin D, but not with camptothecin, augmented the interaction of p53 with Mdm2 and KAP1. Further, KAP1 reduction in actinomycin D-treated cells facilitated cell cycle arrest and negatively affected clonal cell growth. Thus, the reduction of KAP1 levels promotes p53-dependent p21 induction and inhibits cell proliferation in actinomycin D-treated cells. KAP1 may serve as a therapeutic target against cancer in combination with actinomycin D.
Okamoto
Koji
K
National Cancer Center Research Institute, Radiobiology Division, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. kojokamo@gan2.res.ncc.go.jp
Kitabayashi
Issay
I
Taya
Yoichi
Y
D000970:Antineoplastic Agents / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003609:Dactinomycin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005720:Gamma Rays; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000076183:Tripartite Motif-Containing Protein 28; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D002166:Camptothecin