Conditional inactivation of the TGF-β type II receptor using Cre:Lox
Conditional inactivation of the TGF-β type II receptor using Cre:Lox
复制标题
DOI：
10.1002/gene.10046
复制
发表时间：
2002-02-01
期刊：
影响因子：
1.5
通讯作者：
Moses, HL
中科院分区：
文献类型：
--
作者：
Chytil, A;Magnuson, MA;Moses, HL
有确凿的证据表明，TGF-β超家族在哺乳动物发育中起着重要作用。大量的证据来自小鼠的靶向基因失活。例如，Smad 2和Smad 4的破坏导致小鼠的胃周细胞形成致死（Weinstein等人，1998; Sirard等人，1998年）。缺乏Smad 5的动物在E9-11.5之间由于胚胎和胚外缺陷而死亡（Chang等人，1999年）。有趣的是，II型TGF-β受体（TβRII）缺陷的小鼠在10.5 dpc时死亡，具有类似的造血和血管发生缺陷（Oshima et al.，1996），这表明BMP和TGF-β信号传导之间可能存在串扰。这些证据大多来自于证明人类肿瘤中参与TGF-β信号转导的基因失活突变的研究，包括DPC 4/Smad 4、Smad 2和TβRII（Derynck和Akhurst，2001）。据报道，在没有可检测突变的情况下，TβRII表达降低在癌前军团中也很常见（Gobbi et al.，1999年）。TGF-β信号通路的肿瘤抑制作用的其他证据来自对转基因小鼠的研究。乳腺上皮细胞中TGF-β1的过表达抑制癌的发展（Pierce等人，1995年）。乳腺上皮细胞中显性阴性II型TGF-β受体（DNIIR）的表达增加了乳腺癌的发病率（Gorska和Moses，未发表的观察结果）。
There is solid evidence that the TGF-β superfamily plays an important role in mammalian development. A great deal of the evidence comes from targeted gene inactivation in mice. For example, disruption of Smad2 and Smad4 results in perigastrulation lethality in mice (Weinstein et al., 1998; Sirard et al., 1998). Animals lacking Smad5 die between E9–11.5 because of embryonic and extraembryonic defects (Chang et al., 1999). Interestingly, mice deficient in the type II TGF-β receptor (TβRII) die at 10.5 dpc with similar defects in hematopoiesis and vasculogenesis (Oshima et al., 1996), suggesting that there may be cross-talk between BMP and TGF-β signaling.Furthermore, there is compelling evidence indicating that the TGF-β signaling pathway is tumor suppressive. Much of this evidence is derived from studies demonstrating inactivating mutations in human tumors of genes involved in TGF-β signal transduction, including DPC4/Smad4, Smad2, and the TβRII (Derynck and Akhurst, 2001). Decreased TβRII expression in the absence of detectable mutations has also been reported to be common in premalignant legions (Gobbi et al., 1999). Additional evidence for a tumor suppressor role for the TGF-β signaling pathway was derived from studies with genetically modified mice. Overexpression of TGF-β1 in mammary epithelial cells suppresses the development of carcinomas (Pierce et al., 1995). Expression of a dominant negative type II TGF-β receptor (DNIIR) in mammary epithelial cells increases the incidence of mammary carcinomas (Gorska and Moses, unpublished observation).