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Inhibitory Effects of 1,25-Dihydroxyvitamin D₃ on the G₁–S Phase-Controlling Machinery

Institute of Cancer Biology (S.S.J., J.L., J.B.) The Danish Cancer Society, DK-2100 Copenhagen, Denmark; and LEO Pharmaceutical Products (S.S.J., M.W.M., L.B.), DK-21002750 Ballerup, Denmark

Address all correspondence and request for reprints to: Dr. Simon Skjode Jensen, Department of Molecular Biology and Biochemistry, Leo Pharmaceutical Products, Industriparken 55, Ballerup, Denmark 2750.

The nuclear hormone 1,25-dihydroxyvitamin D₃ induces cell cycle arrest, differentiation, or apoptosis depending on target cell type and state. Although the antiproliferative effect of 1,25-dihydroxyvitamin D₃ has been known for years, the molecular basis of the cell cycle blockade by 1,25-dihydroxyvitamin D₃ remains largely unknown. Here we have investigated the mechanisms underlying the G₁ arrest induced upon 1,25-dihydroxyvitamin D₃ treatment of the human breast cancer cell line MCF-7. Twenty-four-hour exposure of exponentially growing MCF-7 cells to 1,25-dihydroxyvitamin D₃ impeded proliferation by preventing S phase entry, an effect that correlated with appearance of the growth-suppressing, hypophosphorylated form of the retinoblastoma protein (pRb), and modulation of cyclin-dependent kinase (cdk) activities of cdk-4, -6, and -2. Time course immunochemical and biochemical analyses of the cellular and molecular effects of 1,25-dihydroxyvitamin D₃ treatment for up to 6 d revealed a dynamic chain of events, preventing activation of cyclin D1/cdk4, and loss of cyclin D3, which collectively lead to repression of the E2F transcription factors and thus negatively affected cyclin A protein expression.

While the observed 10-fold inhibition of cyclin D1/cdk 4-associated kinase activity appeared independent of cdk inhibitors, the activity of cdk 2 decreased about 20-fold, reflecting joint effects of the lower abundance of its cyclin partners and a significant increase of the cdk inhibitor p21^CIP1/WAF1, which blocked the remaining cyclin A(E)/cdk 2 complexes.

Together with a rapid down-modulation of the c-Myc oncoprotein in response to 1,25-dihydroxyvitamin D₃, these results demonstrate that 1,25-dihydroxyvitamin D₃ inhibits cell proliferation by targeting several key regulators governing the G₁/S transition.

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