Jeha S, Luo X N, Beran M, Kantarjian H, Atweh G F
Department of Pediatrics, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Res. 1996 Mar 15;56(6):1445-50.
Phosphoprotein p18 was identified originally on the basis of its very high level of expression in leukemic cells of different lineages. Changes in the level of p18 accumulation and phosphorylation associated with induction of differentiation of leukemic cells suggested a potential role for this phosphoprotein in cellular proliferation and differentiation and possibly in malignant transformation. Recent studies have demonstrated that p18 plays an important role in cell cycle progression by serving as a substrate for p34(cdc2) kinase. These studies showed that inhibition of p18 expression in leukemic cells results in growth retardation and accumulation of cells in G(2)-M. In this study, we explore the potential role of p18 in cellular transformation by investigating the effects of inhibition of p18 expression on the malignant phenotype of K562 erythroleukemia cells. These studies show that antisense inhibition of p18 expression in leukemic cells results in growth arrest at a lower saturation density, loss of serum independence, and loss of anchorage-independent growth in vitro. In addition, inhibition of p18 expression results in a marked inhibition of tumorigenicity of leukemic cells in vivo in the severe combined immune deficiency mouse model. These studies demonstrate that the high level of p18 expression in leukemic cells is necessary for the maintenance of the transformed phenotype and suggest p18 as a potential target for antileukemic interventions.
磷蛋白p18最初是根据其在不同谱系白血病细胞中的高表达水平而被鉴定出来的。与白血病细胞分化诱导相关的p18积累和磷酸化水平的变化表明，这种磷蛋白在细胞增殖和分化以及可能的恶性转化中具有潜在作用。最近的研究表明，p18作为p34(cdc2)激酶的底物，在细胞周期进程中发挥重要作用。这些研究表明，抑制白血病细胞中p18的表达会导致生长迟缓以及细胞在G(2)-M期积累。在本研究中，我们通过研究抑制p18表达对K562红白血病细胞恶性表型的影响，探讨p18在细胞转化中的潜在作用。这些研究表明，白血病细胞中p18表达的反义抑制导致在较低饱和密度下生长停滞、失去血清依赖性以及体外非锚定依赖性生长能力丧失。此外，在严重联合免疫缺陷小鼠模型中，抑制p18表达会导致白血病细胞在体内的致瘤性显著抑制。这些研究表明，白血病细胞中高水平的p18表达对于维持转化表型是必要的，并提示p18作为抗白血病干预的潜在靶点。
