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Cyclin-dependent Kinase Inhibitor p27 as a Mediator of the G₁-S Phase Block Induced by 1,25-Dihydroxyvitamin D₃ in HL60 Cells¹

Department of Laboratory Medicine and Pathology, UMD-New Jersey Medical School and Graduate School of Biomedical Sciences, Newark, New Jersey 07103

Progression of mammalian cells through G₁ is controlled by the concerted action of protein kinases, the activities of which are modulated in both positive (cyclins) and negative [cyclin-dependent kinase inhibitors (CDIs)] manners by families of regulatory proteins. In differentiation of leukemia cells, a G₁ arrest is a common, if not invariable, occurrence and takes place after the appearance of markers of monocytic differentiation in human leukemia HL60 cells treated with 1,25 dihydroxyvitamin D₃ (1,25D₃) at low to moderately high concentrations (F. Zhang et al., Cell Proliferation 27: 643–654, 1994). In the present study, we investigated the protein levels of several G₁ regulatory proteins that are potential mediators of the 1,25D₃-induced G₁ block. During the first 24 h of exposure to a high concentration (4 x 10^-7 M) of 1,25D₃, no increase was noted in the immunodetectable levels of cyclins D1 or E, or CDIs p16^Ink4, p21^Cip1/Waf1, or p27^Kip1, even though monocytic differentiation markers were evident, and a prolongation of G₁ was noted. After 48 h of exposure 4 x 10^-7 M to 1,25D₃, a G₁ to S-phase block progressively increased in parallel with the abundance of the p27^Kip1 CDI. A transient increase in p21^Cip1/Waf1 was noted only at 48 hr. The increase in p27^Kip1 protein level was dependent on the concentration of 1,25D₃ and was accompanied by an increase in cyclin D and E proteins, which normally peak in mid-G₁ and at the G₁ to S-phase transition, respectively. These results indicate that p27^Kip1 protein is a strong candidate for the cell cycle regulator that blocks the entry into the S-phase in 1,25D₃-treated HL60 cells.

¹ Supported by United States Public Health Service Grant RO1-CA 44722 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Laboratory Medicine & Pathology, UMD-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103. Phone: (201) 982-5869; Fax: (201) 982-7293.

Received 10/13/95. Accepted 11/22/95.

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