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The effect of TGFbeta1 on the expression and phosphorylation of key cell-cycle regulators in malignant B cells

机译：TGFbeta1对恶性B细胞中关键细胞周期调节子的表达和磷酸化的影响

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Background:Transforming growth factor beta1 (TGFbeta1) induces growth arrest in many cell types, including B lymphocytes. The inhibitory action of TGFbeta1 is mediated by the deactivation of kinase complexes. The cell-cycle engine is tightly controlled by cyclin-dependent kinase (cdk) inhibitors, which mediate extracellular negative signals, resulting in cell-cycle arrest at different G1 points.Material/Methods:Our experimental DoHH2 cell line model was derived from a patient with malignant non-Hodgkin’s lymphoma (NHL) of follicular origin. We examined the effect of TGFbeta1 on the expression and phosphorylation of key cell-cycle regulators by immunoprecipitation and immunoblotting.Results:After 48 hours of TGFbeta1 (10 ng/ml) treatment, a significantly increased number of DoHH2 cells was retained in G[sub]o[/sub]/G[sub]1[/sub] phase. Our results showed the inhibitory action was associated with hypophosphorylation of pRb on serine 795 (S795) and threonine 373 (T373). We examined the composition of the cdk complexes and the level of cdk inhibitors to explain the inhibitory action of TGFbeta1 on cdk activity. Western blotting showed that the total level of the kinase inhibitor p21 [sup]WAF1[/sup] increased after TGFbeta1 treatment. Our results indicate that a notably high level of p21[sup]WAF1[/sup] was bound to cdk4/6 due to the treatment and that the binding of p21WAF1 was associated with cyclin D-cdk4/6 complex decomposition.Conclusions:Our investigation of the effect of TGFbeta1 on cell-cycle progression of a non-Hodgkin’s lymphoma cell line of follicular lymphoma subtype showed that the TGFbeta1-induced growth arrest of malignant B cells was associated with the activation of CIP/KIP family members of cdk inhibitors.
机译：背景：转化生长因子beta1（TGFbeta1）诱导许多细胞类型（包括B淋巴细胞）的生长停滞。 TGFbeta1的抑制作用是由激酶复合物的失活介导的。细胞周期引擎受到细胞周期蛋白依赖性激酶（cdk）抑制剂的严格控制，该抑制剂介导细胞外负信号，导致细胞周期在不同的G1点停滞。滤泡来源的恶性非霍奇金淋巴瘤（NHL）。我们通过免疫沉淀和免疫印迹检查了TGFbeta1对关键细胞周期调节因子表达和磷酸化的影响。结果：TGFbeta1（10 ng / ml）处理48小时后，G [sub]中保留了明显增加的DoHH2细胞数量] o [/ sub] / G [sub] 1 [/ sub]相。我们的结果表明，抑制作用与pRb对丝氨酸795（S795）和苏氨酸373（T373）的磷酸化作用有关。我们检查了cdk复合物的组成和cdk抑制剂的水平，以解释TGFbeta1对cdk活性的抑制作用。 Western印迹显示，在TGFβ1处理后，激酶抑制剂p21 [WAF1]的总水平增加。我们的结果表明，由于该处理，p21 [sup] WAF1 [/ sup]的高水平与cdk4 / 6结合，而p21WAF1的结合与细胞周期蛋白D-cdk4 / 6复合物的分解有关。 TGFbeta1对滤泡性淋巴瘤亚型非霍奇金淋巴瘤细胞系细胞周期进程的影响表明，TGFbeta1诱导的恶性B细胞生长停滞与cdk抑制剂的CIP / KIP家族成员的激活有关。

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