GADD45 proteins: central players in tumorigenesis.
GADD45 proteins: central players in tumorigenesis.
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DOI：
10.2174/156652412800619978
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发表时间：
2012-06
影响因子：
2.5
通讯作者：
Zerbini LF
中科院分区：
文献类型：
--
作者：
Tamura RE;de Vasconcellos JF;Sarkar D;Libermann TA;Fisher PB;Zerbini LF
生长阻滞和DNA损伤诱导45 （GADD45）蛋白参与许多细胞功能的调控，包括DNA修复、细胞周期控制、衰老和基因毒性应激。然而，促凋亡活性也将GADD45定位为肿瘤发生的重要参与者。新出现的功能证据表明，GADD45蛋白在响应多种刺激时作为肿瘤抑制因子，连接多个细胞信号传导模块。GADD45通路的缺陷可能与恶性肿瘤的发生和发展有关。此外，诱导GADD45的表达是介导多种化疗药物抗癌活性的必要步骤，缺乏GADD45可能会取消其在癌细胞中的作用。在这篇综述中，我们全面讨论了GADD45蛋白的功能，将其调控与细胞周期阻滞、DNA修复和细胞凋亡的效应联系起来。关于它们在肿瘤生长抑制中的重要和核心作用的后果也进行了研究。我们还广泛回顾了最近的文献，以阐明不同的化疗药物如何诱导GADD45基因表达，以及GADD45基因的上调和与不同分子伴侣的相互作用如何有利于癌症化疗和促进新药物的发现。
The Growth Arrest and DNA Damage-inducible 45 (GADD45) proteins have been implicated in regulation of many cellular functions including DNA repair, cell cycle control, senescence and genotoxic stress. However, the pro-apoptotic activities have also positioned GADD45 as an essential player in oncogenesis. Emerging functional evidence implies that GADD45 proteins serve as tumor suppressors in response to diverse stimuli, connecting multiple cell signaling modules. Defects in the GADD45 pathway can be related to the initiation and progression of malignancies. Moreover, induction of GADD45 expression is an essential step for mediating anti-cancer activity of multiple chemotherapeutic drugs and the absence of GADD45 might abrogate their effects in cancer cells. In this review, we present a comprehensive discussion of the functions of GADD45 proteins, linking their regulation to effectors of cell cycle arrest, DNA repair and apoptosis. The ramifications regarding their roles as essential and central players in tumor growth suppression are also examined. We also extensively review recent literature to clarify how different chemotherapeutic drugs induce GADD45 gene expression and how its up-regulation and interaction with different molecular partners may benefit cancer chemotherapy and facilitate novel drug discovery.