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The Requirement for and Changing Composition of the Activating Protein-1 Transcription Factor during Differentiation of Human Leukemia HL60 Cells Induced by 1,25-Dihydroxyvitamin D₃

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

Requests for reprints: George P. Studzinski, Department of Pathology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103. Phone: 973-972-5869; Fax: 973-972-7293; E-mail: studzins{at}umdnj.edu.

The activating protein-1 (AP-1) transcription factor complex is a heterogeneous entity, composed in mammalian cells of dimers chosen from a group of at least eight proteins belonging to three families: jun, fos, and activating transcription factor (ATF). The AP-1 complexes participate in diverse biological processes that include cell proliferation, survival, and differentiation. These seemingly contrasting functions have been attributed to the intensity and duration of the signals provided by AP-1, but the biological consequences of changing composition of the AP-1 complex have not been fully explored. Here, we show that functional AP-1 is required for 1,25-dihydroxyvitamin D₃ (1,25D)-induced monocytic differentiation, and that the composition of the AP-1 protein complex that binds TRE, its cognate DNA element, changes as cells differentiate. In HL60 cells in an early stage of differentiation, the principal AP-1 components detected by gel shift analysis include c-jun, ATF-2, fos-B, fra-1, and fra-2. In cells with a more established monocytic phenotype, the demonstrable AP-1 components are c-jun, ATF-2, jun-B, and fos-B. Following the addition of 1 nmol/L of 1,25D, the cellular content of each of these four proteins markedly increased in a sustained manner, whereas the increases in c-fos, fra-1, fra-2, and jun-D were minimal, if any. Small increases in mRNA levels encoding all AP-1 component proteins, except c-fos, were also noted. These findings provide a basis for the previously found participation of the c-Jun N-terminal kinase pathway in 1,25D-induced differentiation of myeloid leukemia cells, and direct attention to jun-B and fos-B as new cellular therapeutic targets, that may promote replicative quiescence associated with differentiation of malignant cells. (Cancer Res 2006; 66(8): 4202-9)