Reed J C, Meister L, Tanaka S, Cuddy M, Yum S, Geyer C, Pleasure D
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
Cancer Res. 1991 Dec 15;51(24):6529-38.
The bcl2 protooncogene was originally discovered because of its involvement in t(14;18) chromosomal translocations frequently found in non-Hodgkin's lymphomas. The expression of this gene is reported to be highly tissue specific, with bcl2 mRNAs being readily detectable only in hematolymphoid tissues and brain. To explore the possible involvement of bcl2 in neural tumors, we surveyed a variety of tumor cell lines for the presence of the p26-BCL2 protein by immunoprecipitation and immunoblotting methods. Very high levels of BCL2 protein were found in three of nine neuroblastoma (NB) cell lines examined; these levels of p26-BCL2 were comparable to lymphoma cell lines that contain a t(14;18). Despite the impressive relative amounts of BCL2 protein, however, no structural alterations or changes in the methylation status of bcl2 genes were detected in these NB cell lines by conventional Southern blotting. Of the other NB cell lines surveyed, three contained intermediate levels of BCL2 and another three cell lines had little or no detectable BCL2 protein, raising the possibility that determination of relative levels of BCL2 protein may help to segregate neuroblastomas into groups with different biological and clinical characteristics. BCL2 protein levels were not influenced by induction of neuronal differentiation with nerve growth factor in two of the two cell lines examined [SH-SY5Y (high BCL2); GICAN (low BCL2)] and did not correlate with N-MYC gene amplification or expression of nerve growth factor receptors. NB cell lines that contained little or no detectable BCL2 protein, however, tended to contain significant proportions of flat epithelioid cells, whereas bcl2-expressing cell lines were composed primarily of neuronal-like cells, suggesting that expression of this protooncogene correlates with the differentiation characteristics of these tumor cell lines. In addition to NBs, lower levels of BCL2 protein were also found in a variety of other neural crest-derived tumors and tumor cell lines, including some neuroepitheliomas, Ewing's sarcomas, neurofibromas, and melanomas. With regard to tumors of central nervous system origin, bcl2 expression was absent from most medulloblastomas but was detected at moderate to low levels in a retinoblastoma and some glioblastoma multiforme cell lines. Taken together, these findings imply that bcl2 protooncogene expression is differentially regulated within the various lineages of cells that give rise to the nervous system.
bcl2原癌基因最初是因其参与非霍奇金淋巴瘤中常见的t(14;18)染色体易位而被发现的。据报道，该基因的表达具有高度的组织特异性，bcl2 mRNA仅在血液淋巴组织和大脑中易于检测到。为了探究bcl2在神经肿瘤中的可能作用，我们通过免疫沉淀和免疫印迹方法检测了多种肿瘤细胞系中p26 - BCL2蛋白的存在情况。在所检测的9个神经母细胞瘤（NB）细胞系中，有3个细胞系中发现了非常高水平的BCL2蛋白；这些p26 - BCL2水平与含有t(14;18)的淋巴瘤细胞系相当。然而，尽管BCL2蛋白的相对含量令人印象深刻，但通过传统的Southern印迹法在这些NB细胞系中未检测到bcl2基因的结构改变或甲基化状态变化。在所检测的其他NB细胞系中，有3个细胞系含有中等水平的BCL2，另外3个细胞系几乎检测不到或没有可检测到的BCL2蛋白，这增加了一种可能性，即确定BCL2蛋白的相对水平可能有助于将神经母细胞瘤分为具有不同生物学和临床特征的组。在所检测的两个细胞系[SH - SY5Y（高BCL2）；GICAN（低BCL2）]中的两个中，BCL2蛋白水平不受神经生长因子诱导的神经元分化的影响，并且与N - MYC基因扩增或神经生长因子受体的表达无关。然而，几乎检测不到或没有可检测到的BCL2蛋白的NB细胞系往往含有相当比例的扁平上皮样细胞，而表达bcl2的细胞系主要由神经元样细胞组成，这表明该原癌基因的表达与这些肿瘤细胞系的分化特征相关。除了NBs外，在多种其他神经嵴衍生的肿瘤和肿瘤细胞系中也发现了较低水平的BCL2蛋白，包括一些神经上皮瘤、尤因肉瘤、神经纤维瘤和黑色素瘤。关于中枢神经系统起源的肿瘤，大多数髓母细胞瘤中不存在bcl2表达，但在视网膜母细胞瘤和一些多形性胶质母细胞瘤细胞系中检测到中等至低水平的bcl2表达。综上所述，这些发现表明bcl2原癌基因的表达在产生神经系统的各种细胞谱系中受到不同的调节。
