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首页> 外文期刊>Molecular and Cellular Biology >Inhibition of the Raf-1 kinase by cyclic AMP agonists causes apoptosis of v-abl-transformed cells.
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Inhibition of the Raf-1 kinase by cyclic AMP agonists causes apoptosis of v-abl-transformed cells.

机译：环状AMP激动剂对Raf-1激酶的抑制作用会导致v-abl转化的细胞凋亡。

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Here we investigate the role of the Raf-1 kinase in transformation by the v-abl oncogene. Raf-1 can activate a transforming signalling cascade comprising the consecutive activation of Mek and extracellular-signal-regulated kinases (Erks). In v-abl-transformed cells the endogenous Raf-1 protein was phosphorylated on tyrosine and displayed high constitutive kinase activity. The activities of the Erks were constitutively elevated in both v-raf- and v-abl-transformed cells. In both cell types the activities of Raf-1 and v-raf were almost completely suppressed after activation of the cyclic AMP-dependent kinase (protein kinase A [PKA]), whereas the v-abl kinase was not affected. Raf inhibition substantially diminished the activities of Erks in v-raf-transformed cells but not in v-abl-transformed cells, indicating that v-abl can activate Erks by a Raf-1-independent pathway. PKA activation induced apoptosis in v-abl-transformed cells while reverting v-raf transformation without severe cytopathic effects. Overexpression of Raf-1 in v-abl-transformed cells partially protected the cells from apoptosis induced by PKA activation. In contrast to PKA activators, a Mek inhibitor did not induce apoptosis. The diverse biological responses correlated with the status of c-myc gene expression. v-abl-transformed cells featured high constitutive levels of expression of c-myc, which were not reduced following PKA activation. Myc activation has been previously shown to be essential for transformation by oncogenic Abl proteins. Using estrogen-regulated c-myc and temperature-sensitive Raf-1 mutants, we found that Raf-1 activation could protect cells from c-myc-induced apoptosis. In conclusion, these results suggest (i) that Raf-1 participates in v-abl transformation via an Erk-independent pathway by providing a survival signal which complements c-myc in transformation, and (ii) that cAMP agonists might become useful for the treatment of malignancies where abl oncogenes are involved, such as chronic myeloid leukemias.
机译：在这里，我们研究了Raf-1激酶在v-abl癌基因转化中的作用。 Raf-1可以激活包括Mek和细胞外信号调节激酶（Erks）的连续激活的转化信号级联。在v-abl转化的细胞中，内源性Raf-1蛋白在酪氨酸上被磷酸化并显示出高的组成型激酶活性。 Erks的活性在v-raf-和v-abl转化的细胞中均组成性升高。在这两种细胞中，Raf-1和v-raf的活性在激活环AMP依赖性激酶（蛋白激酶A [PKA]）后都几乎被完全抑制，而v-abl激酶则不受影响。 Raf抑制作用实质上减少了在v-raf转化的细胞中Erks的活性，但在v-abl转化的细胞中没有，这表明v-abl可以通过不依赖Raf-1的途径激活Erks。 PKA激活诱导v-abl转化的细胞凋亡，同时还原v-raf转化而没有严重的细胞病变作用。在v-abl转化的细胞中Raf-1的过表达部分保护细胞免受PKA激活诱导的凋亡。与PKA激活剂相反，Mek抑制剂不诱导细胞凋亡。多种生物学反应与c-myc基因表达的状态有关。 v-abl转化的细胞具有高组成水平的c-myc表达，在PKA激活后并未降低。以前已证明Myc激活对于致癌Abl蛋白的转化至关重要。使用雌激素调节的c-myc和温度敏感的Raf-1突变体，我们发现Raf-1激活可以保护细胞免受c-myc诱导的细胞凋亡。总之，这些结果表明：（i）Raf-1通过提供与补体c-myc互补的生存信号，通过Erk独立途径参与了v-abl转化;（ii）cAMP激动剂可能对涉及abl致癌基因的恶性肿瘤的治疗，例如慢性粒细胞白血病。

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