Effect of bcl-2 proto-oncogene expression on cellular sensitivity to tumor necrosis factor-mediated cytotoxicity.
Effect of bcl-2 proto-oncogene expression on cellular sensitivity to tumor necrosis factor-mediated cytotoxicity.
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发表时间：
1993-04
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影响因子：
8
通讯作者：
B. Vanhaesebroeck;John Calvin Reed;D. De Valck;J. Grooten;T. Miyashita;S. Tanaka;R. Beyaert;F. van Roy;W. Fiers
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作者：
B. Vanhaesebroeck;John Calvin Reed;D. De Valck;J. Grooten;T. Miyashita;S. Tanaka;R. Beyaert;F. van Roy;W. Fiers
原癌基因bcl-2（B细胞淋巴瘤/白血病2）的引入和表达已显示通过阻断细胞凋亡或程序性细胞死亡来延长某些造血细胞系在生长因子剥夺后的存活。我们研究了bcl-2表达对细胞对肿瘤坏死因子（TNF）裂解的敏感性的影响，TNF是一种能够诱导几种肿瘤细胞系凋亡的细胞因子。在高度TNF敏感的L929小鼠纤维肉瘤细胞系中引入人bcl-2基因并没有导致TNF敏感性的改变。同样，NIH 3 T3和REF细胞对TNF细胞毒性有抗性，但在与放线菌素D共处理或腺病毒E1 A基因表达后变得对TNF敏感，在bcl-2转染后没有显示出改变的TNF敏感性。尽管内源性bcl-2基因的组成型表达，人MCF 7乳腺癌细胞，以及HL 60早幼粒细胞白血病和U937组织细胞淋巴瘤细胞系被发现是TNF敏感的。这些细胞系的bcl-2过表达衍生物没有获得降低的TNF敏感性，并且仍然表现出TNF诱导的凋亡的核小体间DNA片段化的特征模式。此外，bcl-2的表达在白细胞介素3（IL-3）依赖性髓系32 D保护这些细胞从生长因子剥夺导致的凋亡，但不从TNF诱导的凋亡。这些数据清楚地建立了bcl-2基因表达和细胞对TNF诱导的细胞溶解的敏感性之间的相关性。这些发现在诱导细胞凋亡的不同途径假设的背景下进行了讨论，其中只有一些途径受到bcl-2表达的影响。
Introduction and expression of the proto-oncogene bcl-2 (B-cell lymphoma/leukemia 2) has been shown to extend the survival of certain hematopoietic cell lines after growth factor deprivation, by blocking apoptosis or programmed cell death. We investigated the effect of bcl-2 expression on cellular sensitivity to lysis by tumor necrosis factor (TNF), a cytokine capable of inducing apoptosis in several tumor cell lines. Introduction of the human bcl-2 gene in the highly TNF-sensitive L929 mouse fibrosarcoma cell line did not result in altered TNF sensitivity. Likewise, NIH3T3 and REF cells, which are resistant to TNF cytotoxicity but become TNF sensitive upon cotreatment with actinomycin D or upon expression of the adenovirus E1A gene, did not show altered TNF sensitivity upon bcl-2 transfection. Despite constitutive expression of the endogenous bcl-2 gene, human MCF7 breast carcinoma cells, as well as HL60 promyelocytic leukemia and U937 histiocytic lymphoma cell lines were found to be TNF sensitive. bcl-2-overexpressing derivatives of these cell lines did not acquire reduced TNF sensitivity and still exhibited the characteristic pattern of internucleosomal DNA fragmentation of TNF-induced apoptosis. Moreover, bcl-2 expression in the interleukin 3 (IL-3)-dependent myeloid cell line 32D protected these cells from apoptosis resulting from growth factor deprivation, but not from apoptosis induced by TNF. These data clearly establish the absence of a correlation between bcl-2 gene expression and cellular sensitivity to TNF-induced cell lysis. These findings are discussed in the context of the hypothesis of different pathways for induction of apoptosis, only some of which are affected by bcl-2 expression.