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cis-Diamminedichloroplatinum(II) Cross-Linking of the Human Myeloid Cell Nuclear Differentiation Antigen to DNA in HL-60 Cells following 1,25-Dihydroxy Vitamin D₃-induced Monocyte Differentiation¹

Departments of Biochemistry [M. G., J. A. B., A. W., R. O., R. C. B.] and Pathology [R. C. B.] and Center in Molecular Toxicology [M. G., J. A. B., A. W., R. O., R. C. B.], Vanderbilt University School of Medicine, Nashville, Tennessee 37232; Hoffman-LaRoche Inc., Nutley, New Jersey 07110 [M. U.]; and Department of Cell Biology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655 [J. B. L., G. S. S.]

Protein-DNA interactions of the human myeloid cell nuclear differentiation antigen (MNDA) were examined in vivo in proliferating HL-60 promyelocytic leukemia cells and following induction of differentiation by 1,25-dehydroxyvitamin D₃. Intact cells were treated with the reversible cross-linking agent cis-diamminedichloroplatinum(II) and the MNDA levels in the isolated protein-DNA complexes were determined. Less than 1% of the toal intracellular level of MNDA was cross-linked to DNA in the noninduced proliferating HL-60 cells. Once the cells were induced to differentiate into monocytes, the amount of antigen cross-linked to the DNA increased to over 5% of the total intracellular level. The increased efficiency of cross-linking the MNDA to DNA was specific for monocyte-induced HL-60 differentiation, achieved with three inducers, and was not observed in association with granulocyte-induced differentiation. On a molar basis the phorbol ester (12-O-tetradecanoylphorbol-13-acetate) was the most effective inducer of monocyte differentiation, followed by 1,25-dihydroxy-16-ene-23-ynecholecalciferol which was more effective than 1,25-dihydroxycholecalciferol. A cesium chloride gradient analysis of the nucleic acid-protein fraction isolation from cis-diamminedichloroplatinum(II)-treated, monocyte-induced HL-60 cells documented the authenticity of the association between the MNDA and DNA. The results indicate that a significant level of chromatin reorganization may accompany monocyte-induced differentiation that leads to much higher levels of MNDA-DNA cross-linking to DNA. The expression of the MNDA is restricted to human myeloid cells and the present results indicate that a fraction of this low abundance nuclear protein is specifically located near the DNA [within cis-diamminedichloroplatinum(II) cross-linking distance] and that this association may be modulated specifically during monocyte differentiation.

¹ Supported by NIH Grants CA 37097 and ES 00267.

² To whom requests for reprints should be addressed, at Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232.

Received 5/ 5/89. Revised 9/29/89. Accepted 11/ 8/89.

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