Differential tumor suppressor properties and transforming growth factor-β responsiveness of p57KIP2 in leukemia cells with aberrant p57KIP2 promoter DNA methylation
Differential tumor suppressor properties and transforming growth factor-β responsiveness of p57KIP2 in leukemia cells with aberrant p57KIP2 promoter DNA methylation
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DOI：
10.1038/sj.onc.1209907
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发表时间：
2007-03-01
期刊：
影响因子：
8
通讯作者：
Garcia-Manero, G.
中科院分区：
文献类型：
--
作者：
Kuang, S-Q;Ling, X.;Garcia-Manero, G.
为了研究p57 KIP 2的肿瘤抑制特性是否依赖于其DNA甲基化状态，我们研究了几种应激刺激对具有不同p57 KIP 2启动子DNA甲基化水平的白血病细胞系的影响。在p57 KIP 2启动子未甲基化的细胞中，在用转化生长因子-β、其他细胞因子、高密度培养物或血清撤回刺激后观察到p57 KIP 2再活化，但在甲基化的细胞中未观察到。在这些细胞中，p57 KIP 2的再激活需要使用低甲基化剂或组蛋白去乙酰化酶抑制剂。在p57 KIP 2启动子甲基化的白血病细胞系中过表达p57 KIP 2导致细胞生长停滞和诱导凋亡。相反，p57 KIP 2在部分甲基化细胞中的过表达仅导致细胞生长的中度抑制，并且对细胞凋亡没有影响。用p57 KIP 2短发夹RNA转导表达高水平p57 KIP 2的未甲基化细胞导致细胞增殖增加。这些结果表明，p57 KIP 2在白血病中的肿瘤抑制特性可能取决于该基因固有的启动子DNA甲基化状态。
To investigate if the tumor suppressor properties of p57KIP2 are dependent on its DNA methylation status, we studied the impact of several stress stimuli in leukemic cell lines with different p57KIP2 promoter DNA methylation levels. p57KIP2 reactivation was observed after stimulation with transforming growth factor-beta, other cytokines, high-density culture or serum withdrawal in p57KIP2 promoter unmethylated cells but not in methylated cells. In these cells, p57KIP2 reactivation required the use of a hypomethylating agent or a histone deacetylase inhibitor. Overexpression of p57KIP2 in p57KIP2 promoter methylated leukemic cell lines resulted in cell growth arrest and the induction of apoptosis. In contrast, overexpression of p57KIP2 in partially methylated cells only resulted in a moderate inhibition of cell growth and had no impact on apoptosis. Transduction of unmethylated cells expressing high levels of p57KIP2 with p57KIP2 short hairpin RNA resulted in increased cell proliferation. These results suggest that the tumor suppressive properties of p57KIP2 in leukemia may depend on the intrinsic promoter DNA methylation status of the gene.