p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation
p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation
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DOI：
10.1038/sj.onc.1207422
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发表时间：
2004-04-29
期刊：
影响因子：
8
通讯作者：
Beier, F
中科院分区：
文献类型：
--
作者：
Halawani, D;Mondeh, R;Beier, F
软骨肉瘤是第二常见的原发性骨骼恶性肿瘤。这种肿瘤类型对放射治疗和目前可用的化疗具有高度抗性，从而限制了手术切除的治疗选择。因此，确定负责软骨肉瘤细胞增殖的机制对于开发新的治疗策略至关重要。在这里，我们证明了一个显着减少大鼠软骨肉瘤细胞增殖后的药物抑制剂（SB 202190和PD 169316）的p38丝裂原活化蛋白（MAP）激酶治疗。在试图剖析可能的机制，我们研究了p38抑制对细胞周期基因启动子活性的影响。令人惊讶的是，p38抑制导致所有三个D型细胞周期蛋白启动子的活性上调。此外，p38抑制剂诱导细胞周期抑制剂p21（waf 1/cip 1）的转录增加。正如预期的那样，细胞周期蛋白A基因的启动子活性，这是下游的D-型细胞周期蛋白和p21在细胞周期的进展，强烈减少p38抑制剂。这些效果是独立的环AMP反应元件，并赋予近150个核苷酸的细胞周期蛋白A启动子。转录降低伴随着p38抑制后细胞周期蛋白A蛋白水平的大大降低。这些观察结果表明，软骨肉瘤细胞周期进程的p38信号复杂的调节，并建议p38 MAP激酶通路的组件可能是有效的目标，在这些肿瘤的治疗。
Chondrosarcomas represent the second most frequent class of primary skeletal malignancies. This tumor type is highly resistant to radiation therapy and currently available chemotherapies, thereby limiting treatment choice to surgical resection. Identifying the mechanisms responsible for chondrosarcoma cell proliferation is therefore crucial for the development of new treatment strategies. Here, we demonstrate a significant reduction in rat chondrosarcoma cell proliferation following treatment with pharmacological inhibitors (SB202190 and PD169316) of p38 mitogen-activated protein (MAP) kinases. In an attempt to dissect possible mechanisms, we investigated the effect of p38 inhibition on promoter activity of cell-cycle genes. Surprisingly, p38 inhibition resulted in upregulation of the activities of all three D-type cyclin promoters. In addition, p38 inhibitors induced increased transcription of the cell-cycle inhibitor p21(waf1/cip1). As expected, promoter activity of the cyclin A gene, which lies downstream of D-type cyclins and p21 in cell-cycle progression, was strongly reduced by p38 inhibitors. These effects were independent of a cyclic AMP response element and conferred by the proximal 150 nucleotides of the cyclin A promoter. Decreased transcription was accompanied by greatly reduced cyclin A protein levels upon p38 inhibition. These observations indicate complex regulation of chondrosarcoma cell-cycle progression by p38 signaling, and suggest that components of p38 MAP kinase pathways may be effective targets in the treatment of these tumors.