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LEFTY1是一种SMAD双重抑制因子
作者:小柯机器人 发布时间:2020/7/22 23:00:42

美国斯坦福大学Michael F. Clarke小组的一项最新工作发现,LEFTY1是SMAD双重抑制因子,可促进乳祖细胞生长和肿瘤发生。相关论文于2020年7月20日在线发表在《细胞—干细胞》杂志上。

研究人员证明LEFTY1是NODAL/SMAD2信号的分泌抑制因子。BMP7是一种具有环境相关功能的NODAL拮抗剂,由基底细胞产生并抑制祖细胞增殖,它可以抑制SMAD2和SMAD5信号传导从而促进正常和恶性乳腺上皮细胞的长期增殖。
 
在正常小鼠的上皮中,LEFTY1在腔细胞和稀有基底细胞中与BMP7对立表达,从而促进导管分支;LEFTY1与BMPR2结合,来抑制BMP7诱导的SMAD5激活,而这种LEFTY1-BMPR2相互作用在三阴性乳腺癌异种移植物中对肿瘤起始细胞是特异的,因为其依赖于LEFTY1来生长。这些结果表明,LEFTY1是内源性SMAD双重抑制因子,而抑制其功能可能是乳腺癌治疗的靶点。
 
据介绍,SMAD途径控制上皮细胞的增殖,而通过SMAD成员传递TGF-β和BMP信号对乳腺发育和体内稳态具有明显的影响。
 
附:英文原文

Title: LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis

Author: Maider Zabala, Neethan A. Lobo, Jane Antony, Luuk S. Heitink, Gunsagar S. Gulati, Jessica Lam, Natesh Parashurama, Kassandra Sanchez, Maddalena Adorno, Shaheen S. Sikandar, Angera H. Kuo, Dalong Qian, Tomer Kalisky, Sopheak Sim, Linus Li, Frederick M. Dirbas, George Somlo, Aaron Newman, Stephen R. Quake, Michael F. Clarke

Issue&Volume: 2020-07-20

Abstract: SMAD pathways govern epithelial proliferation, and transforming growth factor β (TGF-βand BMP signaling through SMAD members has distinct effects on mammary developmentand homeostasis. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling,is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5signaling to promote long-term proliferation of normal and malignant mammary epithelialcells. In contrast, BMP7, a NODAL antagonist with context-dependent functions, isproduced by basal cells and restrains progenitor cell proliferation. In normal mouseepithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposesBMP7 to promote ductal branching. LEFTY1 binds BMPR2 to suppress BMP7-induced activationof SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cellsin triple-negative breast cancer xenografts that rely on LEFTY1 for growth. Theseresults suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressingits function may represent a therapeutic vulnerability in breast cancer.

DOI: 10.1016/j.stem.2020.06.017

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30284-8

期刊信息

Cell Stem Cell:《细胞—干细胞》,创刊于2007年。隶属于细胞出版社,最新IF:21.464
官方网址:https://www.cell.com/cell-stem-cell/home
投稿链接:https://www.editorialmanager.com/cell-stem-cell/default.aspx