Galectin-1 interacts with the α5β1 fibronectin receptor to restrict carcinoma cell growth via induction of p21 and p27
Galectin-1 interacts with the α5β1 fibronectin receptor to restrict carcinoma cell growth via induction of p21 and p27
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DOI：
10.1074/jbc.m411580200
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发表时间：
2005-11-04
影响因子：
4.8
通讯作者：
Rosewicz, S
中科院分区：
文献类型：
--
作者：
Fischer, C;Sanchez-Ruderisch, H;Rosewicz, S
半乳糖凝集素家族成员的表面结合具有将不同聚糖结构与生长调节联系起来的潜力。因此，我们解决了半乳糖凝集素-1（Gal-1）在一组癌细胞系中的抗增殖潜力。我们发现Gal-1在不同来源的上皮肿瘤细胞系中具有生长抑制作用，并提供证据表明这种作用需要与α 5 β 1整合素的功能相互作用。抗增殖作用源于Ras-MEK-ERK途径的抑制和p27的连续转录诱导。我们已经进一步确定了两个Sp1结合位点的p27启动子作为Gal-1的反应至关重要。Gal-1对Ras-MEK-ERK级联的抑制增加了Sp1的反式激活和DNA结合，这是由于减少了Sp1的苏氨酸磷酸化。此外，Gal-1诱导p21转录并选择性地增加p27蛋白的稳定性。Gal-1介导的p27和p21的积累抑制细胞周期蛋白依赖性激酶2的活性，并最终导致G（1）细胞周期停滞和生长抑制。这些数据定义了Gal-1通过与α 5 β 1整联蛋白的碳水化合物依赖性相互作用调节上皮肿瘤细胞稳态的新机制。
Surface binding of galectin family members has the potential to link distinct glycan structures to growth regulation. Therefore, we addressed the antiproliferative potential of galectin-1 (Gal-1) in a panel of carcinoma cell lines. We discovered growth inhibition by Gal-1 in epithelial tumor cell lines from different origins and provide evidence that this effect requires functional interaction with the alpha 5 beta 1 integrin. Antiproliferative effects result from inhibition of the Ras-MEK-ERK pathway and consecutive transcriptional induction of p27. We have further identified two Sp1-binding sites in the p27 promoter as crucial for Gal-1 responsiveness. Inhibition of the Ras-MEK-ERK cascade by Gal-1 increased Sp1 transactivation and DNA binding due to reduced threonine phosphorylation of Sp1. Furthermore, Gal-1 induced p21 transcription and selectively increased p27 protein stability. Gal-1-mediated accumulation of p27 and p21 inhibited cyclin-dependent kinase 2 activity and ultimately resulted in G(1) cell cycle arrest and growth inhibition. These data define a novel mechanism whereby Gal-1 regulates epithelial tumor cell homeostasis via carbohydrate-dependent interaction with the alpha 5 beta 1 integrin.