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Background
Transforming growth factor β1 (TGFβ1) is a potent inhibitor of epithelial cell growth, thus playing an important role in tissue homeostasis. Most carcinoma cells exhibit a reduced sensitivity for TGFβ1 mediated growth inhibition, suggesting TGFβ1 participation in the development of these cancers. The tumor suppresor gene DPC4/SMAD4, which is frequently inactivated in carcinoma cells, has been described as a key player in TGFβ1 mediated growth inhibition. However, some carcinoma cells lacking functional SMAD4 are sensitive to TGFβ1 induced growth inhibition, thus requiring a SMAD4 independent TGFβ1 pathway.Results
Here we report that mature TGFβ1 is a ligand for the integrin αVβ6, independent of the common integrin binding sequence motif RGD. After TGFβ1 binds to αVβ6 integrin, different signaling proteins are activated in TGFβ1-sensitive carcinoma cells, but not in cells that are insensitive to TGFβ1. Among others, interaction of TGFβ1 with the αVβ6 integrin resulted in an upregulation of the cell cycle inhibitors p21/WAF1 and p27 leading to growth inhibition in SMAD4 deleted as well as in SMAD4 wildtype carcinoma cells.Conclusions
Our data provide support for the existence of an alternate TGFβ1 signaling pathway that is independent of the known SMAD pathway. This alternate pathway involves αVβ6 integrin and the Ras/MAP kinase pathway and does not employ an RGD motif in TGFβ1-sensitive tumor cells. The combined action of these two pathways seems to be necessary to elicit a complete TGFβ1 signal.6.
我叫吴兆成,家住武城县杨庄乡位官屯。一家4口人,有妻子和两个女儿,家庭和睦而温馨。正当大女儿将要出嫁,小女儿要外出打工,家庭生活条件一年好似一年,全家对未来生活充满美好憧憬的时候,人生历程给了我一个不大不小的难题,这就是死神的挑战。我为此拼搏数年至今,总算赢来了人生最宝贵的财富——生存与健康。 相似文献
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目的∶ 研究下咽鳞癌患者治疗前免疫细胞的分布特征及其对预后的影响。方法∶收集 2009年11月至2019年 10 月昆明医科大学第三附属医院收治的650 例下咽鳞癌患者临床资料,同时纳入650 例健康志愿者作为对照组,采用SPS 21.0对下咽鳞癌患者治疗前和对照组两组间的免疫细胞数进行比较。根据免疫细胞的分布特征对下咽鳞癌患者治疗前机体的免疫状况进行分类,运用Kaplan-Meier 法和Log-rank 检验对不同免疫状态的患者进行生存分析,比较不同免疫状态对下咽鳞癌患者生存率的影响,以 P<0.05 为差异有统计学意义。结果∶与对照组相比,下咽鳞癌组 CD3+T细胞、CD4+T细胞、CD4+/CD8+比值、NK 细胞、CIK 细胞数显著降低,CD8+T细胞显著升高。650例下咽鳞癌患者根据治疗前免疫细胞的分布特征分为5类∶第Ⅰ类免疫耐受型(221 例,34%)、第Ⅱ类免疫低下型(143 例,22%)、第Ⅲ类肿瘤反应型(169 例,26%)、第ⅣV类免疫消耗型(6 例,10%)、第V类免疫亢进型(52 例, 8%);免疫细胞特征分布为第1~V类患者的中位生存期分别为 16个月(95% C∶14.11~17.88)、11 个月(95% CI∶ 9.11~12.88)、32个月(95% CI∶29.9~34.41)、29个月(95% CI∶23.39~34.61)和23个月(95% CI∶15.%~ 30.04)。结论∶下咽鳞癌患者机体存在细胞免疫功能紊乱,不同免疫状态的下咽鳞癌患者预后不同,免疫细胞分布为第 ⅢI 类的患者预后最好,分布为第 Ⅳ 类、第Ⅴ类的患者预后较好,分布为第 1类、第Ⅱ类的患者预后最差。 相似文献
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Transforming growth factor β (TGFβ) plays an important role in animal development and many cellular processes. A variety of cellular functions that are required for tumor metastasis are controlled by integrins, a family of cell adhesion receptors. Overexpression of αVβ6 integrin is associated with lymph node metastasis of gastric carcinomas. It has been demonstrated that a full TGFβ1 signal requires both αVβ6 integrin and SMAD pathway. TGFβ1 binds to αVβ6 via the DLXXL motif, a freely accessible amino acid sequence in the mature form of TGFβ1. Binding of mature TGFβ1 to αVβ6 leads to immobilization and tyrosine phosphorylation of proteins, which are associated with focal adhesions, a hallmark of integrin-mediated signal transduction. Here, we show that binding of mature TGFβ1 recruits the mitogen-activated protein kinase kinase kinase 1 (MEKK1), a mediator of c-Jun activation, and the extracellular signaling-regulated kinase-1 (Erk1) to focal adhesions. In addition, the p21-activated kinase 1 (PAK1) is associated with focal adhesions and differentially phosphorylated upon TGFβ1 stimulation. We conclude that TGFβ1 activates c-Jun via the MEKK1/p38 MAP kinase pathway and influences cytoskeletal organization. These finding may provide a link between TGFβ1 and the metastatic behavior of cancers. 相似文献
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《癌变.畸变.突变》2009,21(3)
《癌变·畸变·突变》是中国科学技术协会主管、中国环境诱变剂学会(国家一级学会)主办的学术期刊,于1989年创刊,双月刊,国内外公开发行。本刊为中国科技论文统计源期刊(中国科技核心期刊),被《中国科技论文与引文数据库》(CSTPC)、《中国核心期刊(遴选)数据库》、《中文科技期刊数据库》、《中国生物医学文献数据库》、《中文生物医学期刊文献数据库》、《中国学术期刊综合评价数据库》等10种国内著名数据库和《中国生物学文摘》、《中国学术期刊文摘》等学术文摘期刊收录。 相似文献
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