Abstract 3915: Inhibition of cdc2 is linked to PMA-induced cell differentiation

Abstract

Abstract The critical role of cdc2 (CDK1) in G2-M transition of the cell cycle control in mammalian cells has been well documented. Recent studies have also demonstrated that cdc2 is capable of driving G1 progress and G1-S transition via association with multiple interphase cyclins and through the interactions with Rb proteins. However, whether this pluripotent CDK regulates cell differentiation is unclear. Thus, the effect of phorbol 12-myristate 13-acetate (PMA) on cell differentiation and the expression of cdc2 in a human myeloid leukemia cell line, TF-1a, was investigated. When TF-1a cells were treated with 10−5, 10−6, and 10−7 PMA for 48 and 72h, they showed marked (≥50%) macrophage-like changes, evidenced by significant decrease in nucleus/cytoplasm ratio and increase (1-3 folds) in the expression of IL-1β, a macrophage marker. PMA treatment also caused time-dependent inhibition of cdc2 in both cytosol and nucleus of the cells, with a maximal inhibition being observed by 48 and 72h, which paralleled with the cell differentiation course. In contrast, there was no significant cell differentiation and inhibition of cdc2 being observed in control human myeloid leukemia TF-1 cells treated with PMA. Previous studies suggest that prolonged activation of MAPK pathway is linked to cell differentiation. PMA treatment also rapidly induced phosphorylation of MAPK kinases (MEK and ERK), which persisted for 24h, after which phosphorylated MEK and ERK were returned to base level, while the expression of cdc2 was still significantly downregulated, as compared with the control cells treated with DMSO. Pretreatment of TF-1a cells with sense cdc2 oligo nucleotides partially inhibited PMA-induced differentiation and upregulation of IL-1β. Taken together, our data suggest that MAPK pathway may be responsible for initiation of cell differentiation whereas inhibition of cdc2 is required for late differentiation of TF-1a cells in response to PMA stimulation. Whether activation of the MAPK pathway inhibits expression of cdc2 is currently under investigation (Supported by Faculty Incentive Grant and NIH-NIGMS MBRS RISE: R25 GM059244-13, Barry University). Note: This abstract was not presented at the meeting. Citation Format: Daria Vasilyeva, Pairat Dolinsky, Shashana Fielder, Alice Nakasone, Gerhild Packert, Xiaotang Hu. Inhibition of cdc2 is linked to PMA-induced cell differentiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3915. doi:10.1158/1538-7445.AM2015-3915