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Autocrine growth inhibitors of keratinocytes and their significance in carcinogenesis

角质形成细胞自分泌生长抑制剂及其在癌变中的意义

基本信息

批准号：
09670243
负责人：
KATO Mitsuyasu
金额：
$ 2.37万
依托单位：
Japanese Foundation for Cancer Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

(1) Functions of TGF-beta pathway-restricted SMADs : We identified a splice variant of Smad2 which omitted exon 3.Smad2DELTAexon3 had a transcriptional activity more potent than wild-type Smad2 and similar to Smad3, when p3TP-lux was used as a reporter.Smad2DELTAexon3 had an activity to bind to a Smad binding element in the p3TP promoter, which Smad3 can bind to but Smad2 can not.These results suggested that the peptide coded by exon 3 of Smad2 interfered with the direct DNA binding of Smad2.We also found that TGF-beta activated both Smad2 and Smad3 in HaCaT cells, and activin activated Smad3 as potent as TGF-beta did, but the activation of Smad2 by activin was less potent than that by TGF-beta.(2) Inhibition of TGF-beta signals by a mutant Smad3 : A mutation of Smad2 identified in a case of colon cancer was reconstructed on the corresponding residue of Smad3.This mutant Smad3D407E had a dominant negative effect on TGF-beta signals.Expression of Smad3D407E conferred invasive growth potential on HaCaT cells as well as resistance to the growth inhibitory effects of TGF-beta.(3) Disruption of TGF-beta signals in cancer cells : Patients of papillary thyroid microadenocarcinoma with a positive staining for TGF-beta in the primary lesions had higher incidence of distant metastasis than negative cases.(4) Target genes of TGF-beta signals : c-Myc was identified to be an essential target of SMADs in growth inhibitory signals of TGF-beta in keratinocytes.We also identified a new early responsive gene to TGF-beta.This gene coded a nuclear protein of 19 kDa with an isoelectric point of 10.9.(5) Physiological function of TGF-beta signals : TGF-beta was suggested to be involved in epithelial cell migration during the corneal wound healing process.

(1)Smad2途径限制性Smads的功能：我们发现了Smad2的一个剪接变异体，它省略了外显子3。以p3TP-lux为报告基因时，Smad2DELTAexon 3的转录活性高于野生型Smad2，与Smad3相似。Smad2DELTAexon3具有与p3TP启动子中的Smad结合元件结合的活性，Smad3可以与Smad3结合，而Smad2不能。这些结果表明，Smad2外显子3编码的多肽干扰了Smad2与DNA的直接结合。我们还发现，在HaCaT细胞中，转化生长因子-β同时激活了Smad2和Smad3，并激活了Smad3(2)突变的Smad3对转化生长因子-β信号的抑制：在一例结肠癌中发现的Smad2突变是在相应的Smad3残基上重建的。突变的Smad3D407E对转化生长因子-β信号具有明显的负效应。Smad3D407E的表达赋予HaCaT细胞侵袭性生长潜力，并抵抗转化生长因子-β的生长抑制作用。(3)癌细胞转化生长因子-β信号的中断：原发灶中转化生长因子-β染色阳性的乳头状甲状腺微腺癌患者(4)转化生长因子-β信号的靶基因：在角质形成细胞中，c-Myc是Smads生长抑制信号的重要靶点。我们还发现了一个新的对转化生长因子-β有早期反应的基因，该基因编码19 kDa的核蛋白，等电点为10.9。(5)转化生长因子-β信号的生理功能：推测转化生长因子-β参与了角膜创伤愈合过程中上皮细胞的迁移过程。