Makover D, Cuddy M, Yum S, Bradley K, Alpers J, Sukhatme V, Reed J C
Department of Internal Medicine, University of Pennsylvania, Philadelphia 19104.
Oncogene. 1991 Mar;6(3):455-60.
The expression and function of several proto-oncogenes were examined in a human acute T cell leukemia line, JURKAT, during phorbol ester-induced terminal differentiation. Treating JURKAT cells with the phorbol ester tetradecanoyl phorbol acetate (TPA) inhibited their proliferation and induced expression of the gene for the interleukin 2 receptor alpha chain (IL2R-alpha), consistent with previous reports. In unstimulated proliferating JURKAT cells, high levels of C-MYC, N-RAS, and BCL2 mRNAs were found that diminished rapidly following TPA-induced cessation of growth. In contrast, accumulation of mRNAs for the C-FOS, C-JUN, and EGR-1 genes increased markedly in TPA-treated cells and preceded the induction of IL2R-alpha mRNA. Expression of C-MYB, C-RAF-1, C-LCK, C-FYN, and C-FGR proto-oncogenes was relatively unchanged. To explore directly the function of two of these protooncogenes in regulating the growth of JURKAT T cells, we stably transferred C-MYC and BCL2 expression plasmids into these cells. Despite sustained expression of C-MYC, BCL2, or the combination of these protooncogenes, TPA continued to inhibit JURKAT cell growth and to induce IL2R expression. Thus, although C-MYC and BCL2 proto-oncogene expression correlated with proliferation in TPA-treated JURKAT cells, continuous over-expression of even the combination of these oncogenes was insufficient for abrogating the effects of TPA in these leukemic T cells. Because human lymphoid malignancies frequently contain chromosomal translocations that deregulate the expression of C-MYC and BCL2, our findings could have relevance for attempts to induce terminal differentiation of leukemic cells by in vitro exposure of patients' bone marrow cells to phorbol esters.
在佛波酯诱导的终末分化过程中，对人急性T细胞白血病细胞系JURKAT中几种原癌基因的表达和功能进行了检测。用佛波酯十四酰佛波醇乙酸酯（TPA）处理JURKAT细胞可抑制其增殖，并诱导白细胞介素2受体α链（IL2R-α）基因的表达，这与先前的报道一致。在未受刺激的增殖性JURKAT细胞中，发现高水平的C-MYC、N-RAS和BCL2 mRNA，在TPA诱导生长停止后迅速减少。相反，在TPA处理的细胞中，C-FOS、C-JUN和EGR-1基因的mRNA积累显著增加，并先于IL2R-α mRNA的诱导。C-MYB、C-RAF-1、C-LCK、C-FYN和C-FGR原癌基因的表达相对未变。为了直接探究其中两种原癌基因在调节JURKAT T细胞生长中的功能，我们将C-MYC和BCL2表达质粒稳定转入这些细胞。尽管C-MYC、BCL2或这些原癌基因的组合持续表达，但TPA仍继续抑制JURKAT细胞生长并诱导IL2R表达。因此，尽管C-MYC和BCL2原癌基因的表达与TPA处理的JURKAT细胞中的增殖相关，但即使这些癌基因的组合持续过表达也不足以消除TPA对这些白血病T细胞的影响。由于人类淋巴恶性肿瘤经常包含使C-MYC和BCL2表达失调的染色体易位，我们的发现可能与通过体外将患者骨髓细胞暴露于佛波酯来诱导白血病细胞终末分化的尝试相关。
