Analysis of the mechanism for suppression of childhood leukemia via ARF-p53 pathway

ARF是一种抑癌基因产物，可能通过p53依赖性途径保护细胞免于白血病转化。在这项研究中，我们进行了分析的淋巴细胞表面标志物的ARF无效的淋巴细胞和造血细胞集落形成骨髓细胞培养的细胞因子的几种组合的存在下。然而，ARF-空细胞并不具有特定的表面标记和生长优势相比，野生型细胞。ARF使细胞在存在适当的侧支信号的情况下对凋亡敏感。因此，我们分析ARF依赖的细胞凋亡机制，研究ARF对肿瘤的抑制作用。我们证明，ARF诱导p53野生型细胞中的细胞凋亡依赖于细胞凋亡。我们还发现，ARF引起线粒体释放细胞色素c，降低线粒体膜电位，激活caspase-9前体诱导细胞凋亡。这种促凋亡细胞调节似乎是通过上调两组促凋亡/抗凋亡线粒体蛋白Bax/Bcl-2和Bim/Bcl-2的比率而引起的。而ARF通过p53依赖性途径下调Bcl-2，血清饥饿诱导Bax和Bim上调。

ARF, a tumor suppressor gene product, is seemed to protect cells from leukemic transformation via p53-dependent pathway. In this study, we performed the analysis of lymphocyte surface markers on ARF-null lymphocytes and examined hematopoietic cell colony formation from bone marrow cells cultured in the presence of several combinations of the cytokines. However, ARF-null cells did not possess specific surface makers and growth advantage compared to wild-type cells. ARF sensitizes cells to apoptosis in the presence of appropriate collateral signals. Therefore, we analyzed the mechanism of ARF-dependent apoptosis to study the role of ARF on tumor suppression. We demonstrated that ARF induces mitochondria-dependent apoptosis in p53 wild-type cells. We also found that ARF evokes cytochrome c release from mitochondria, decreases mitochondrial membrane potential and activates pro-caspase-9 to induce apoptosis. This pro-apoptotic cellular modulation appeared to be brought about by upregulation of the ratio of two sets of pro-apoptotic/anti-apoptotic initochondrial proteins, Bax/Bcl-2 and Bim/Bcl-2. Whereas downregulation of Bcl-2 by ARF was via a p53-dependent pathway, Bax and Bim upregulation was induced by serum starvation.