Leukemogenic AML1-ETO fusion protein upregulates expression of connexin 43: The role in AML 1-ETO-induced growth arrest in leukemic cells
Leukemogenic AML1-ETO fusion protein upregulates expression of connexin 43: The role in AML 1-ETO-induced growth arrest in leukemic cells
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DOI：
10.1002/jcp.20695
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发表时间：
2006-09-01
影响因子：
5.6
通讯作者：
Chen, Guo-Qiang
中科院分区：
文献类型：
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作者：
Li, Xi;Xu, Ya-Bei;Chen, Guo-Qiang
AMLI-ETO是一种由染色体易位t（8;21）产生的融合蛋白，常与急性髓性白血病（AML）相关。除了阻断分化外，AML 1-ETO还显示诱导AML细胞的生长停滞，这不利于携带t（8;21）易位的白血病发生。然而，其确切的机制仍不清楚。在这里，我们提供了第一个证明，条件表达AMLI-ETO的蜕皮激素诱导系统显着增加连接蛋白43（CX43）的表达，连同生长停滞在G，在白血病U937细胞。我们还表明，CX 43诱导抑制U937细胞在G期的增殖，而通过小干扰RNA（siRNA）抑制CX 43的表达有效地克服了AML 1-ETO在白血病细胞中的生长抑制作用。此外，AMLI-ETO或CX43诱导通过抑制其降解来提高细胞周期负调节因子P27（kip 1）蛋白，这被针对CX43的siRNA拮抗。综上所述，我们的数据表明，CX43可能通过P27（kip 1）蛋白的积累在AML 1-ETO诱导的生长停滞中发挥作用。在AML 1-ETO阳性的AML患者中，CX43及其相关基因的潜在突变或/和表观遗传学改变值得探索。
AMLI-ETO, a fusion protein generated by the chromosomal translocation t(8;21), is frequently associated with acute myeloid leukemia (AML). In addition to blocking differentiation, AML1 -ETO is also shown to induce growth arrest in AML cells, which is unfavorable for leukemogenesis harboring the t(8;21) translocation. However, its precise mechanism is still unclear. Here we provide the first demonstration that the conditional expression of AMLI-ETO by the ecdysone-inducible system dramatically increases the expression of connexin 43 (CX43), together with growth arrest at G, phase in leukemic U937 cells. We also show that the CX43 induction inhibits the proliferation of U937 cells at G, phase, while the suppression of CX43 expression by small interfering RNA (siRNA) effectively overcomes the growth-inhibitory effect of AML1-ETO in leukemic cells. Furthermore, either AMLI-ETO or CX43 induction elevates cell-cycle negative regulator P27(kip1) protein by inhibiting its degradation, which is antagonized by siRNA against CX43. Taken together, ourdata indicate that CX43 plays a role in AML1-ETO-induced growth arrest possibly through the accumulation of P27(kip1) protein. The potential mutation or/and epigenetic alterations of CX43 and its related gene(s) deserve to be explored in AML1-ETO-positive AML patients.