Differential effects of BCL-2 on survival and proliferation of human B-lymphoma cells following γ-irradiation
Differential effects of BCL-2 on survival and proliferation of human B-lymphoma cells following γ-irradiation
复制标题
BCL-2 对 γ 辐射后人 B 淋巴瘤细胞存活和增殖的不同影响
作者：
A. Milner;R. Grand;A. Vaughan;R. Armitage;C. Gregory
Bcl-2可以抑制由各种刺激（包括辐射）诱导的凋亡，并且其在肿瘤细胞中的存在预期将指示不良预后。然而，表达Bcl-2的肿瘤通常是低级别的，对治疗有高度反应。为了研究这一明显的矛盾，我们在体外分析了伯基特淋巴瘤（BL）细胞在Bcl-2存在和不存在的情况下对γ射线照射的反应。高水平表达Bcl-2可促进照射后BL细胞的存活。然而，一个显着比例的Bcl-2拯救的细胞随后经历了一段时间后，在文化的凋亡。此外，在不同的BL系中，发现Bcl-2促进或抑制γ射线照射后的长期增殖活性。这种增殖的差异调节与Bcl-2对细胞周期的差异作用和p53状态的差异相关。因此，照射后一周，BL细胞只表达野生型p53（wt/wt）已被逮捕在G1期，而那些与突变等位基因（wt/mu）被逮捕在细胞周期的所有阶段。Bcl-2拯救的细胞，随后经历凋亡的比例减少了CD 40在wt/wt BL细胞照射时的连接，但不是在wt/mu细胞。CD 40连接减少G1期阻滞和细胞凋亡并行。这些结果表明，虽然Bcl-2可以延迟γ射线照射后BL细胞的凋亡，但该蛋白质也可以引起生长停滞，从而促进凋亡。Bcl-2介导的γ射线照射细胞的长期存活可能取决于p53状态，并需要额外的死亡抑制或生长促进信号。
Bcl-2 can inhibit apoptosis induced by a variety of stimuli, including radiation and its presence in tumour cells would be expected to indicate poor prognosis. Bcl-2-expressing tumours, however, are often low-grade and highly responsive to therapy. To investigate this apparent paradox, we analysed in vitro the responses of Burkitt lymphoma (BL) cells to γ-irradiation in the presence and absence of Bcl-2. High-level expression of Bcl-2 was shown to promote BL cell survival following irradiation. However, a significant proportion of Bcl-2-rescued cells subsequently underwent apoptosis after an extended period in culture. In addition, in different BL lines, Bcl-2 was found either to promote or to inhibit long-term proliferative activity following γ-irradiation. This differential regulation of proliferation correlated both with differential effects of Bcl-2 on the cell cycle and with differences in p53 status. Thus, by one week after irradiation, BL cells expressing only wild-type p53 (wt/wt) had arrested in G1, whereas those with a mutant allele (wt/mu) were arrested in all phases of the cell cycle. The proportion of Bcl-2-rescued cells that subsequently underwent apoptosis was reduced by ligation of CD40 at the time of irradiation in wt/wt BL cells, but not in wt/mu cells. CD40-ligation reduced both G1-arrest and apoptosis in parallel. These results indicate that, whilst Bcl-2 can delay apoptosis in BL cells following γ-irradiation, the protein can also cause growth-arrest and thereby promote apoptosis. Long-term survival following Bcl-2-mediated rescue of γ-irradiated cells may depend on p53 status and require additional death-repressing or growth-promoting signals.