Gadd45a functions as a promoter or suppressor of breast cancer dependent on the oncogenic stress.
Gadd45a functions as a promoter or suppressor of breast cancer dependent on the oncogenic stress.
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DOI：
10.1158/0008-5472.can-10-2177
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Liebermann DA
中科院分区：
文献类型：
--
作者：
Tront JS;Huang Y;Fornace AJ Jr;Hoffman B;Liebermann DA
Gadd45a在调节细胞对包括致癌应激在内的各种应激刺激反应的应激传感器中起着关键作用。我们报道了应激感受器Gadd45a基因通过促进JNK介导的细胞凋亡和p38介导的衰老在RAS诱导的乳腺肿瘤发生中发挥肿瘤抑制作用。相反，我们在这里表明，Gadd45a通过Gsk3β/β-catenin信号负性调控MMP10，促进Myc驱动的乳腺癌，导致肿瘤血管增加和生长。这些新的发现表明，Gadd45a作为肿瘤的促进者或抑制者的功能依赖于致癌压力，并通过不同的信号通路介导。总而言之，这些新的发现强调了致癌改变的类型在应激反应基因如何在肿瘤发生的启动和发展过程中发挥作用的重要性。由于Gadd45a是BRCA1和P53的靶点，这些发现对BRCA1/P53的肿瘤抑制功能有一定的影响。
Gadd45a plays a pivotal role as a stress sensor that modulates cellular responses to various stress stimuli, including oncogenic stress. We reported that the stress sensor Gadd45a gene functions as a tumor suppressor in Ras-driven breast tumorigenesis via increasing JNK-mediated apoptosis and p38-mediated senescence. In contrast, here, we show that Gadd45a promotes Myc-driven breast cancer by negatively regulating MMP10 via GSK3 β/β-catenin signaling, resulting in increased tumor vascularization and growth. These novel findings indicate that Gadd45a function as either tumor promoter or suppressor is dependent on the oncogenic stress and is mediated via distinct signaling pathways. Collectively, these novel findings highlight the significance of the type of oncogenic alteration on how stress response genes function during initiation and progression of tumorigenesis. Since gadd45a is a target for BRCA1 and p53, these finding have implications regarding BRCA1/p53 tumor suppressor functions.