Regulation of Drosophila metamorphosis by xenobiotic response regulators.
Regulation of Drosophila metamorphosis by xenobiotic response regulators.
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通过异种生物反应调节剂对果蝇变态的调节。
DOI：
10.1371/journal.pgen.1003263
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Kerppola TK
中科院分区：
文献类型：
--
作者：
Deng H;Kerppola TK
哺乳动物 Nrf2-Keap1 和同源果蝇 CncC-dKeap1 蛋白复合物调节对外源化合物的转录反应以及天然细胞和发育过程。这些蛋白质在异生素反应和发育中的功能之间的关系尚不清楚。我们研究了发育过程中受 CncC 和 dKeap1 调节的基因以及调节其功能的信号转导途径。 CncC 和 dKeap1 在许多组织的细胞核内富集，与报道的 Keap1 和 Nrf2 在培养的哺乳动物细胞中的细胞质定位相反。 CncC 和 dKeap1 占据多线染色体上蜕皮激素调节的早期泡。唾液腺中 CncC 或 dKeap1 的缺失选择性地减少了早期 puff 基因的转录。前胸腺中的 CncC 和 dKeap1 缺失以及胚胎中的 cncCK6/K6 和 dKeap1EY5/EY5 功能缺失突变减少了蜕皮激素生物合成基因的转录。相比之下，dKeap1 缺失和 dKeap1EY5/EY5 功能丧失突变分别增强了幼虫和胚胎中的异生素反应基因转录。前胸腺中 CncC 或 dKeap1 的消耗通过降低幼虫蜕皮类固醇水平来延迟化蛹。 CncC 耗竭抑制了前胸腺中组成型 Ras 信号传导引起的过早化蛹和发育停滞；相反，组成型 Ras 信号传导改变了 CncC 在多线染色体上占据的基因座，并激活了这些基因座上的基因转录。 CncC 和 dKeap1 对蜕皮激素生物合成和蜕皮激素调节基因转录的影响，以及 CncC 在前胸腺 Ras 信号传导中的作用，确立了这些蛋白质在协调昆虫变态的神经内分泌轴中的功能。人类 Nrf2-Keap1 和果蝇 CncC-dKeap1 蛋白复合物在对外来化学物质的反应和发育过程中发挥作用。我们发现 CncC 和 dKeap1 通过调节控制幼虫转化为蛹的主要激素的产生和作用来控制果蝇发育。在激素反应细胞中，CncC 和 dKeap1 与激素激活的基因结合。当这些细胞中 CncC 或 dKeap1 的数量减少时，这些基因就无法有效激活。当生成激素的器官中 CncC 或 dKeap1 的量减少时，其产物生成激素的基因就无法有效激活。由于产生的激素较少，幼虫变成蛹的时间更长，而且产生的蛹更大。减少 CncC 拦截先前识别的化蛹信号的数量。 Nrf2 是导致小鼠癌症的相同信号所必需的。 CncC 和 dKeap1 对控制激素产生的基因和不同器官中激素开启的基因的影响表明它们在果蝇幼虫转化为蛹的过程中具有多种作用。
Mammalian Nrf2-Keap1 and the homologous Drosophila CncC-dKeap1 protein complexes regulate both transcriptional responses to xenobiotic compounds as well as native cellular and developmental processes. The relationships between the functions of these proteins in xenobiotic responses and in development were unknown. We investigated the genes regulated by CncC and dKeap1 during development and the signal transduction pathways that modulate their functions. CncC and dKeap1 were enriched within the nuclei in many tissues, in contrast to the reported cytoplasmic localization of Keap1 and Nrf2 in cultured mammalian cells. CncC and dKeap1 occupied ecdysone-regulated early puffs on polytene chromosomes. Depletion of either CncC or dKeap1 in salivary glands selectively reduced early puff gene transcription. CncC and dKeap1 depletion in the prothoracic gland as well as cncCK6/K6 and dKeap1EY5/EY5 loss of function mutations in embryos reduced ecdysone-biosynthetic gene transcription. In contrast, dKeap1 depletion and the dKeap1EY5/EY5 loss of function mutation enhanced xenobiotic response gene transcription in larvae and embryos, respectively. Depletion of CncC or dKeap1 in the prothoracic gland delayed pupation by decreasing larval ecdysteroid levels. CncC depletion suppressed the premature pupation and developmental arrest caused by constitutive Ras signaling in the prothoracic gland; conversely, constitutive Ras signaling altered the loci occupied by CncC on polytene chromosomes and activated transcription of genes at these loci. The effects of CncC and dKeap1 on both ecdysone-biosynthetic and ecdysone-regulated gene transcription, and the roles of CncC in Ras signaling in the prothoracic gland, establish the functions of these proteins in the neuroendocrine axis that coordinates insect metamorphosis. Human Nrf2-Keap1 and the fruit fly CncC-dKeap1 protein complexes function both in response to foreign chemicals and in development. We found that CncC and dKeap1 control fruit fly development by regulating the production and actions of the principal hormone that controls the transformation of larvae into pupae. In hormone-responsive cells, CncC and dKeap1 bound to the genes that are activated by the hormone. When the amount of CncC or dKeap1 in these cells was reduced, the genes were not activated efficiently. When the amount of CncC or dKeap1 was reduced in the organ where the hormone is made, the genes whose products make the hormone were not activated efficiently. Because less hormone was made, it took longer for the larvae to turn into pupae, and the resulting pupae were bigger. Reduction of the amount of CncC intercepted previously identified signals for pupation. Nrf2 is required for the same signals to cause cancer in mice. The effects of CncC and dKeap1 both on genes that control hormone production and on genes that are switched on by the hormone in different organs indicate that they have multiple roles in the transformation of fruit fly larvae into pupae.
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影响因子：
14.9
作者：
Malhotra D;Portales-Casamar E;Singh A;Srivastava S;Arenillas D;Happel C;Shyr C;Wakabayashi N;Kensler TW;Wasserman WW;Biswal S
通讯作者：
Biswal S
影响因子：
3.6
作者：
Bobilev, Irene;Novik, Victoria;Danilenko, Michael
通讯作者：
Danilenko, Michael
影响因子：
14.9
作者：
Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
通讯作者：
Bell DA
DOI：
10.1016/j.cub.2010.01.038
发表时间：
2010-03-09
期刊：
Current biology : CB
影响因子：
--
作者：
Halme A;Cheng M;Hariharan IK
通讯作者：
Hariharan IK
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M