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Up-Regulation of Egr1 by 1,25-Dihydroxyvitamin D₃ Contributes to Increased Expression of p35 Activator of Cyclin-Dependent Kinase 5 and Consequent Onset of the Terminal Phase of HL60 Cell Differentiation

Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey

Advances in differentiation therapy of cancer are likely to depend on improved understanding of molecular events that underlie cell differentiation. We reported recently that cyclin-dependent kinase (Cdk)5 and p35Nck5a (p35) are expressed in human leukemia HL60 cells induced to differentiate to monocytes by an exposure to 1,25-dihydroxyvitamin D₃ (1,25D₃), form a complex, and this complex has kinase activity (F. Chen and G. P. Studzinski, Blood 2001;97:3763). This laboratory has also provided evidence that the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway is active in the early (24–48 h) stages of HL60 cell differentiation induced by 1,25D₃ but declines in the later, terminal phase of this form of differentiation (X. Wang and G. P. Studzinski, J Cell Biochem 2001;80:471). We examine now the hypothesis that Egr1 protein contributes to the up-regulation of p35 gene transcription and, thus, activated Cdk5/p35 kinase phosphorylates and inactivates mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1). Our data show that in 1,25D₃-treated cells, p35 and Egr1 protein levels are elevated in a dose-dependent manner at the onset of the late stage of differentiation. We show also that 1,25D₃ treatment of HL60 cells markedly increases the binding of Egr1 to an element in the p35 gene promoter, whereas transfection of an excess of this Egr1-binding oligonucleotide ("promoter decoy") reduces p35 gene transcription and cell differentiation. Additionally, Cdk5/p35 phosphorylates MEK1 and inhibits its ability to phosphorylate its downstream target Erk2. These data suggest that in 1,25D₃-treated HL60 cells, Egr1 up-regulates p35 gene transcription and that Cdk5/p35 kinase inactivates the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway by phosphorylation of MEK1, and this contributes to terminal differentiation of these cells.

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