Inhibition of Shc/Grb2 protein-protein interaction suppresses growth of B104-1-1 tumors xenografted in nude mice.
Actinomycin D was revealed as an inhibitor of Shc/Grb2 interaction in cell lines from our recent study. Shc and Grb2 proteins are important molecules in Ras signaling pathways leading to cellular differentiation and proliferation, which require dramatic morphological changes. It was detected by transmission electron microscopy that actinomycin D induced significant changes in cellular ultrastructures of B104-1-1 cells and confirmed that the changes were due to inhibition of Shc/Grb2 interaction by actinomycin D rather than its inhibitory effect on transcription. Because actinomycin D was dispersed mainly in cytoplasm and Shc peptide (synthetic 13 amino acid tyrosine phosphorylated polypeptide) successfully displaced actinomycin D binding to its cellular targets while the other polypeptide from PDGF receptor could not. We examined the effect of actinomycin D on growth of B104-1-1 tumor xenografted in nude mice. Tumor growth was inhibited in vivo after treatment with this inhibitor. Efficacy was correlated with a reduction in the levels of Shc/Grb2 binding in excised tumors. These results suggest that actinomycin D inhibited Shc/Grb2 interaction in B104-1-1 tumor xenografted in nude mice.
Kim
Hyae-Kyeong
HK
Korea Research Institute of Bioscience and Biotechnology, 52 Uendong Yusung Taejon, 305-333, Republic of Korea.
Jeong
Moon-Jin
MJ
Kong
Mi-Young
MY
Han
Mi Young
MY
Son
Kwang-Hee
KH
Kim
Hwan Mook
HM
Hong
Su Hyung
SH
Kwon
Byoung-Mog
BM
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology / Q000627:therapeutic use*; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000187:drug effects*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D003609:Dactinomycin; D051380:GRB2 Adaptor Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C495949:Grb2 protein, mouse; C528024:SHC1 protein, human; C528034:Shc1 protein, mouse