Osteopontin regulates ubiquitin-dependent degradation of Stat1 in murine mammary epithelial tumor cells
Osteopontin regulates ubiquitin-dependent degradation of Stat1 in murine mammary epithelial tumor cells
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DOI：
10.1593/neo.07463
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发表时间：
2007-09-01
期刊：
影响因子：
4.8
通讯作者：
Kuo, Paul C.
中科院分区：
文献类型：
--
作者：
Gao, Chengjiang;Mi, Zhiyong;Kuo, Paul C.
背景资料：骨桥蛋白（OPN）是一种分泌性糖蛋白，其通过与整合素（主要是α（v）β（3））和CD 44受体结合来介导细胞-基质相互作用和细胞信号传导。OPN调节细胞粘附、趋化性、巨噬细胞介导的IL-10抑制、应激依赖性血管生成、凋亡预防和肿瘤细胞的锚定非依赖性生长。然而，定义OPN在肿瘤进展和转移中的作用的分子机制尚不完全清楚。研究方法：在这项研究中，我们使用了一个系统的4 T1和4 T07小鼠乳腺上皮肿瘤细胞系，这是不同的转移表型和骨桥蛋白表达。4 T1表达OPN并发生血原性转移，而4 T07不表达OPN，具有高度致瘤性，但不能转移。结果如下：我们的研究结果表明，OPN通过泛素-蛋白酶体途径调节Stat 1蛋白降解，从而改变干扰素-γ依赖性生长抑制和p21表达。我们确定在这种情况下，关键的Stat泛素E3连接酶的STAT相互作用的LIM蛋白。结论：OPN调节Stat 1依赖性功能，如在小鼠乳腺上皮细胞系4 T1和4 T07中的生长抑制和p21表达。在肿瘤生物学背景下，OPN和Stat 1之间的这种关系以前尚未研究过。
Background: Osteopontin ( OPN) is a secreted glycoprotein that mediates cell - matrix interactions and cellular signaling by binding with integrin ( primarily alpha(v)beta(3)) and CD44 receptors. OPN regulates cell adhesion, chemotaxis, macrophage-directed IL-10 suppression, stress-dependent angiogenesis, apoptosis prevention, and anchorage-independent growth of tumor cells. However, the molecular mechanisms that define the role of OPN in tumor progression and metastasis are incompletely understood. Methods: In this study, we use a system of 4T1 and 4T07 murine mammary epithelial tumor cell lines that are divergent in both metastatic phenotype and OPN expression. 4T1 expresses OPN and hematogeneously metastasizes, whereas 4T07 does not express OPN and is highly tumorigenic but fails to metastasize. Results: Our results demonstrate that OPN regulates Stat1 protein degradation through the ubiquitin - proteasome pathway to alter interferon-gamma-dependent growth inhibition and p21 expression. We identify Stat-interacting LIM protein as the critical Stat ubiquitin E3 ligase in this setting. Conclusions: OPN regulates Stat1-dependent functions, such as growth inhibition and p21 expression, in the murine mammary epithelial cells lines 4T1 and 4T07. This relationship between OPN and Stat1 in the context of tumor biology has not been previously examined.