Association of p93c-fes tyrosine protein kinase with granulocytic/monocytic differentiation and resistance to differentiating agents in HL-60 leukemia cells.
A 93-kDa tyrosine protein kinase (p93) identified previously as the gene product of the c-fes proto-oncogene, is highly expressed in HL-60 leukemia cells induced to differentiate to the granulocyte or monocyte phenotype. We have now studied the relationship of p93 to the differentiation process by using a dimethyl sulfoxide (DMSO)-resistant subline of HL-60 cells (HL-60/DMSO) or the parental cell line treated with peptide or protein substrates of p93. Treatment of HL-60/DMSO cells with DMSO induced neither differentiation nor the expression of p93; however, cotreatment with IFN-alpha and DMSO resulted in partial differentiation and the concomitant induction of p93 activity. Treatment of wild-type HL-60 cells by the coaddition of the p93 substrates poly(Glu,Tyr)1:1, poly(Glu,Tyr)4:1, poly(Glu,Ala,Tyr)6:3:1, angiotensin II or vasoactive intestinal peptide with DMSO or IFN-tau partially blocked differentiation and concurrently diminished the induction of p93 activity. The inhibitory concentrations of the p93 substrates were related to their Km values. These results indicate that there is an obligatory association between the expression of p93 and granulocyte/monocyte differentiation in this cell line.
Yu
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Laboratory of Biological Chemistry, National Cancer Institute, Bethesda, Maryland 20892.
Grant
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Glazer
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RI
D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology; D008970:Molecular Weight; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D007370:Interferon Type I; D007527:Isoenzymes; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014660:Vasoactive Intestinal Peptide; D011505:Protein-Tyrosine Kinases; D004121:Dimethyl Sulfoxide