Saleem A, Yuan Z M, Taneja N, Rubin E, Kufe D W, Kharbanda S M
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 1995 Apr 15;154(8):4150-6.
The early growth response 1 (EGR-1) gene is induced by mitogenic and differentiating signals in diverse cell types. The present studies have examined the effects of TNF-alpha on the induction of EGR-1 expression in human myeloid leukemia cells and the potential cytoplasmic signaling cascades that transduce TNF-induced signals to the nucleus. The results demonstrate that treatment of HL-60 cells with TNF is associated with the transient induction of the EGR-1 gene. The results also demonstrate that TNF treatment is associated with activation of the serine/threonine kinase, pp90rsk, which acts upstream to EGR-1 gene induction. Partial purification of pp90rsk by affinity chromatography demonstrated an increase in S6 peptide phosphorylation in response to TNF treatment. Because TNF activates sphingomyelin hydrolysis, we also studied the effects of sphingomyelinase (SMase) on induction of EGR-1 and pp90rsk. The results demonstrate that SMase also activates pp90rsk and induces EGR-1 gene expression. Previous work has demonstrated that mitogen-activated protein (MAP) kinase activates pp90rsk. The present studies further show that treatment with TNF or SMase is associated with induction of both the pp42/44 MAP and the related Jun kinases. Induction of pp42/44 MAP kinase activity is temporally related to activation of pp90rsk and the EGR-1 gene. These findings support the involvement of an MAP kinase/pp90rsk/EGR-1 cascade in the response of myeloid leukemia cells to TNF.
早期生长反应1（EGR-1）基因可被多种细胞类型中的促有丝分裂和分化信号所诱导。本研究检测了肿瘤坏死因子-α（TNF-α）对人髓系白血病细胞中EGR-1表达诱导的影响，以及将TNF诱导信号转导至细胞核的潜在细胞质信号级联反应。结果表明，用TNF处理HL-60细胞与EGR-1基因的短暂诱导有关。结果还表明，TNF处理与丝氨酸/苏氨酸激酶pp90rsk的激活有关，该激酶在EGR-1基因诱导的上游起作用。通过亲和层析对pp90rsk进行部分纯化表明，响应TNF处理，S6肽磷酸化增加。由于TNF激活鞘磷脂水解，我们还研究了鞘磷脂酶（SMase）对EGR-1和pp90rsk诱导的影响。结果表明，SMase也激活pp90rsk并诱导EGR-1基因表达。先前的研究表明，丝裂原活化蛋白（MAP）激酶激活pp90rsk。本研究进一步表明，用TNF或SMase处理与pp42/44 MAP激酶和相关的Jun激酶的诱导有关。pp42/44 MAP激酶活性的诱导在时间上与pp90rsk和EGR-1基因的激活有关。这些发现支持了MAP激酶/pp90rsk/EGR-1级联反应参与髓系白血病细胞对TNF的反应。
