The atonal proneural transcription factor links differentiation and tumor formation in Drosophila.
The atonal proneural transcription factor links differentiation and tumor formation in Drosophila.
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DOI：
10.1371/journal.pbio.1000040
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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;De Geest N;Aerts S;Leenaerts I;Marynen P;Hassan BA
末端细胞命运的获得和分化的开始是由特定细胞类型的主控基因指导的。在癌症进展过程中经常观察到分化丧失，但其潜在的原因和机制仍然知之甚少。我们验证了这样一种假设，即主要的分化调节因子可能是肿瘤形成的关键调节因子。利用果蝇的功能丧失和功能获得分析，我们描述了果蝇视网膜中无性转录因子的一个关键的抗癌功能，无性转录因子指示组织分化。在肿瘤的背景下，无性激素通过JNK应激反应途径调节细胞的增殖和死亡。结合ATONAL的哺乳动物同源基因Atoh1是肿瘤抑制基因的证据，我们的数据支持ATO在肿瘤发生中的一个关键的、进化上保守的功能。在胚胎发育过程中，细胞变得越来越特化，这个过程被称为分化。与正常的成年细胞相比，癌细胞--如胚胎细胞--表现出较少的分化特性。据推测，终末分化的获得有助于抑制肿瘤的形成；然而，没有直接证据支持这一假说。长期以来，果蝇的眼睛发育一直被用作研究控制分化的遗传因素的模型。最近，眼睛发育也被用于研究肿瘤是如何形成和发展的。在这项研究中，我们使用这个模型来证明指导特定组织分化的基因，如无机盐，可以作为肿瘤抑制因子，抑制这些组织中肿瘤的形成和发展。失去这样的基因会产生肿瘤，而激活它们可以强烈地抑制这些肿瘤。我们在果蝇的眼睛中建立了癌症和分化启动之间的直接遗传联系。
The acquisition of terminal cell fate and onset of differentiation are instructed by cell type–specific master control genes. Loss of differentiation is frequently observed during cancer progression, but the underlying causes and mechanisms remain poorly understood. We tested the hypothesis that master regulators of differentiation may be key regulators of tumor formation. Using loss- and gain-of-function analyses in Drosophila, we describe a critical anti-oncogenic function for the atonal transcription factor in the fly retina, where atonal instructs tissue differentiation. In the tumor context, atonal acts by regulating cell proliferation and death via the JNK stress response pathway. Combined with evidence that atonal's mammalian homolog, ATOH1, is a tumor suppressor gene, our data support a critical, evolutionarily conserved, function for ato in oncogenesis. During embryonic development, cells become more and more specialized, and this process is referred to as differentiation. In contrast to normal adult cells, cancer cells—like embryonic cells—display fewer differentiated properties. It has been postulated that the acquisition of terminal differentiation helps inhibit tumor formation; however, no direct evidence for this hypothesis was available. The development of the eye in the fruit fly, Drosophila melanogaster, has long been used as a model for studying genetic factors controlling differentiation. More recently, eye development has also been used to study how tumors can form and progress. In this study, we used this model to show that genes, such as atonal, that instruct the differentiation of specific tissues can act as tumor suppressers and inhibit the formation and progression of tumors in those tissues. Losing such genes can generate tumors, whereas activating them can strongly inhibit these tumors. We establish a direct genetic link between cancer and the initiation of differentiation in theDrosophila eye.
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影响因子：
9.8
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
通讯作者：
Hassan BA
影响因子：
64.8
作者：
Reya, T;Clevers, H
通讯作者：
Clevers, H
影响因子：
64.5
作者：
JARMAN, AP;GRAU, Y;JAN, YN
通讯作者：
JAN, YN
影响因子：
5.3
作者：
Sukhanova, Madina J.;Deb, Dilip K.;Du, Wei
通讯作者：
Du, Wei
影响因子：
82.9
作者：
Palomero, Teresa;Sulis, Maria Luisa;Ferrando, Adolfo A.
通讯作者：
Ferrando, Adolfo A.