Inhibition of human hematopoietic tumor formation by targeting a repressor Myb-KRAB to DNA.
In many hematopoietic malignancies, c-Myb, a nuclear transcription factor of hematopoietic cells, is an activated oncogene. To achieve a specific inhibition of hematopoietic tumor growth, an inducible fusion protein consisting of the Myb DNA binding domain (DBD) and the active repressor domain KRAB, the Krüppel-associated box of the developmental zinc-finger protein KOX-1, was generated. The MybDBD-KRAB fusion protein is a potent repressor of Myb-induced gene expression from Myb-responsive reporter genes containing several Myb binding sites. MybDBD-KRAB expressed in the human hematopoietic promyelocytic cell line HL60 significantly reduces cell proliferation by inducing apoptosis. Expression of MybDBD-KRAB in subcutaneously injected HL60 cells leads to inhibition of tumor formation in nude mice. The MybDBD-KRAB effect is specific to cell lines expressing c-Myb. It is conceivable to fuse the KRAB domain to other DBDs of oncogenic transcription factors and target them to their respective DNA response elements to selectively drive tumor cells into apoptosis.
Nawrath
M
M
Institute of Medical Virology, University of Zurich, Switzerland.
Pavlovic
J
J
Moelling
K
K
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002455:Cell Division / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D020570:Genes, myb / Q000235:genetics*; D005822:Genetic Vectors; D018922:HL-60 Cells / Q000378:metabolism* / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000517:prevention & control / Q000628:therapy*; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014410:Tumor Stem Cell Assay / Q000379:methods; D016335:Zinc Fingers / Q000235:genetics*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins