NB4, a human acute promyelocytic leukemia cell line expressing the promyelocyte-retinoic acid receptor alpha (PML-RAR alpha) hybrid protein was treated with RAR- and retinoid X receptor (RXR)-selective analogs to determine their effects on cell proliferation, retinoblastoma (RB) tumor-suppressor protein phosphorylation, and differentiation. An RAR- or just RAR alpha-selective analog alone induced similar cell population growth arrest, cell cycle arrest without restriction to G1, hypophosphorylation of RB, and myelomonocytic cell surface differentiation marker expression (CD11b). In addition, an RAR alpha antagonist could inhibit the effects of the RAR alpha agonist completely. The RAR alpha-selective analog-elicited response was attenuated by simultaneous addition of various RXR-selective analogs. In contrast, each of the RXR-selective analogs was unable to induce any of the cellular responses analyzed. The growth arrest of NB4 cells is not G1-restricted and occurs at all points in the cell cycle. Cells growth arrested by treatment with an RAR alpha-selective analog show primarily hypophosphorylated RB. When these cells are sorted into G1 or S + G2/M subpopulations by flow cytometry, hypophosphorylated RB protein was in G1 as well as S + G2/M cells. This suggests that the hypophosphorylated RB protein may be mediating the growth arrest of NB4 cells at all points in the cell cycle. These results are consistent with an involvement of PML-RAR alpha and/or RAR alpha in the transduction of the retinoid signal in NB4 cells.
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