Atonal homolog 1 is a tumor suppressor gene.
Atonal homolog 1 is a tumor suppressor gene.
复制标题
DOI：
10.1371/journal.pbio.1000039
复制
发表时间：
2009-02-24
期刊：
影响因子：
9.8
通讯作者：
Hassan BA
中科院分区：
文献类型：
--
作者：
Bossuyt W;Kazanjian A;De Geest N;Van Kelst S;De Hertogh G;Geboes K;Boivin GP;Luciani J;Fuks F;Chuah M;VandenDriessche T;Marynen P;Cools J;Shroyer NF;Hassan BA
结肠癌占每年所有癌症死亡人数的10%以上。我们从果蝇和先前哺乳动物Atoh1同源物（也称为Math1或Hath1）的体外研究中获得的遗传证据表明，Atonal组的前缘碱性螺旋-环-螺旋转录因子具有抗肿瘤功能。我们研究小鼠Atoh1和人Atoh1在体内是否作为肿瘤抑制基因。小鼠的基因敲除以及小鼠和人类癌细胞系的分子分析支持ATOH1的肿瘤抑制功能。ATOH1可能通过激活Jun n -末端激酶信号通路，通过调节增殖和凋亡来拮抗肿瘤的形成和生长。此外，结直肠癌和默克尔细胞癌患者表现出遗传性和表观遗传性ATOH1功能丧失突变。我们的数据表明，ATOH1可能是组织中致癌突变的早期靶标，在那里它指导细胞分化。像大多数癌症一样，结肠癌表现出分化的丧失，这种特性越强，癌症的侵袭性就越强。这表明，在这些肿瘤形成过程中，分化能力的丧失可能是一个关键的早期事件。结肠上皮中指导分泌细胞命运分化的关键基因ATOH1在果蝇、小鼠和人类中高度保守。我们想知道ATOH1是否可能是导致小鼠和人类结肠癌的关键因素。我们的研究表明，小鼠结肠特异性ATOH1的缺失足以引发结肠癌，并且大多数人类结肠癌也具有失活的ATOH1。在培养的人类结肠癌细胞中重新激活ATOH1会导致这些细胞停止分裂并自杀。由于这种表观遗传沉默基因的再激活可以使用小化合物来实现，因此研究ATOH1的作用可能会在未来提供治疗途径。结肠分化的主要调控因子是结肠癌的肿瘤抑制基因。
Colon cancer accounts for more than 10% of all cancer deaths annually. Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1 (Atoh1, also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors. We asked whether mouse Atoh1 and human ATOH1 act as tumor suppressor genes in vivo. Genetic knockouts in mouse and molecular analyses in the mouse and in human cancer cell lines support a tumor suppressor function for ATOH1. ATOH1 antagonizes tumor formation and growth by regulating proliferation and apoptosis, likely via activation of the Jun N-terminal kinase signaling pathway. Furthermore, colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations. Our data indicate that ATOH1 may be an early target for oncogenic mutations in tissues where it instructs cellular differentiation. Like most cancers, colon cancer displays a loss of differentiation, and the stronger this property, the more aggressive the cancer. This suggests that the loss of the capacity to differentiate may be a critical and possibly early event during the formation of these tumors. The key gene instructing secretory cell fate differentiation in the epithelium of the colon, namely Atonal homolog 1 (ATOH1), is highly conserved in flies, mice, and humans. We asked whether ATOH1 could be a pivotal factor in causing colon cancer in mice and humans. Our studies show that colon-specific loss of ATOH1 in mice is sufficient to trigger colon cancer and that the majority of human colon cancers also have an inactivated ATOH1. Reactivating ATOH1 in cultured human colon cancer cells causes these cells to stop dividing and to commit suicide. Since reactivation of this epigenetically silenced gene can be achieved using small chemical compounds, studying how ATOH1 acts may offer therapeutic avenues in the future. A master regulator of differentiation in the colon is a tumor suppressor gene for colon cancer.
登录
查看更多内容
影响因子：
50.3
作者：
Kouros-Mehr, Hosein;Bechis, Seth K.;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
64.8
作者：
BenArie, N;Bellen, HJ;Zoghbi, HY
通讯作者：
Zoghbi, HY
影响因子：
56.9
作者：
MOSER, AR;PITOT, HC;DOVE, WF
通讯作者：
DOVE, WF
DOI：
10.1073/pnas.0501600102
发表时间：
2005-10-04
影响因子：
11.1
作者：
Kim, JW;Kim, MJ;Choi, EJ
通讯作者：
Choi, EJ
影响因子：
5
作者：
Colnot, S;Niwa-Kawakita, M;Perret, C
通讯作者：
Perret, C