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Absence of Phorbol Ester-induced Down-Regulation of myc Protein in the Phorbol Ester-tolerant Mutant of HL-60 Promyelocytes¹

Department of Internal Medicine, Iowa City Veterans Administration Medical Center and University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242

The human promyelocytic leukemia cell line HL-60 has an amplified number of copies of the protooncogene c-myc. It is induced to differentiate by exposure to the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA). We have developed a mutant phorbol ester-tolerant (PET) line of HL-60 which undergoes a transient growth arrest but does not differentiate when exposed to TPA (Macfarlane et al., Br. J. Haematol., 68: 291–302, 1988). The defect is not due to a general failure of TPA-induced phosphorylation. In this paper, we show that exposing phorbol estersensitive (S) HL-60 cells to TPA caused the disappearance of the c-myc protein antigen (detected on Western blots) in 4 h, whereas TPA had no effect on the c-myc protein content of PET cells. Dimethyl sulfoxide caused the rapid disappearance of the myc antigen in both cells. PET cells had slightly more copies of the c-myc gene detected on Southern blots than S cells. c-myc mRNA was equally unstable in both cells, as determined by Northern blots following actinomycin D. TPA induced the down-regulation of c-myc mRNA in S cells to a greater extent than in PET cells. Dimethyl sulfoxide caused a rapid down-regulation of c-myc mRNA in both cell lines. This shows that PET cells have a defect in the mechanism by which protein kinase C regulates c-myc transcription. Our results provide further evidence that reduction in c-myc expression is necessary for differentiation to occur in HL-60 cells.

¹ This work was supported by a Merit Review Grant from the Veterans Administration.

² Recipients of NIH Training Grant HL 07344.

³ Present address: Washington University School of Medicine, Barnard Cancer Center, St. Louis, MO 63110.

⁴ Present address: University of Washington School of Medicine, Division of Hematology-Oncology, Seattle, WA 98105.

⁵ To whom requests for reprints should be addressed, at Dept. of Internal Medicine, Division of Hematology-Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242.

Received 11/ 2/88. Revised 6/ 5/89. Accepted 6/29/89.

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