Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Derqui-Pilar, Buenos Aires 1629, Argentina.
Proc Natl Acad Sci U S A. 2020 Dec 22;117(51):32594-32605. doi: 10.1073/pnas.2004470117. Epub 2020 Dec 7.
Inducible transcriptional programs mediate the regulation of key biological processes and organismal functions. Despite their complexity, cells have evolved mechanisms to precisely control gene programs in response to environmental cues to regulate cell fate and maintain normal homeostasis. Upon stimulation with proinflammatory cytokines such as tumor necrosis factor-α (TNF), the master transcriptional regulator nuclear factor (NF)-κB utilizes the PPM1G/PP2Cγ phosphatase as a coactivator to normally induce inflammatory and cell survival programs. However, how PPM1G activity is precisely regulated to control NF-κB transcription magnitude and kinetics remains unknown. Here, we describe a mechanism by which the ARF tumor suppressor binds PPM1G to negatively regulate its coactivator function in the NF-κB circuit thereby promoting insult resolution. ARF becomes stabilized upon binding to PPM1G and forms a ternary protein complex with PPM1G and NF-κB at target gene promoters in a stimuli-dependent manner to provide tunable control of the NF-κB transcriptional program. Consistently, loss of ARF in colon epithelial cells leads to up-regulation of NF-κB antiapoptotic genes upon TNF stimulation and renders cells partially resistant to TNF-induced apoptosis in the presence of agents blocking the antiapoptotic program. Notably, patient tumor data analysis validates these findings by revealing that loss of strongly correlates with sustained expression of inflammatory and cell survival programs. Collectively, we propose that PPM1G emerges as a therapeutic target in a variety of cancers arising from ARF epigenetic silencing, to loss of ARF function, as well as tumors bearing oncogenic NF-κB activation.
诱导性转录程序介导关键生物过程和机体功能的调节。尽管它们很复杂，但细胞已经进化出机制来精确控制基因程序，以响应环境线索来调节细胞命运并维持正常的体内平衡。在受到促炎细胞因子（如肿瘤坏死因子-α（TNF））刺激后，主要转录调节剂核因子（NF）-κB 利用 PPM1G/PP2Cγ 磷酸酶作为共激活因子来正常诱导炎症和细胞存活程序。然而，PPM1G 活性如何被精确调节以控制 NF-κB 转录幅度和动力学仍然未知。在这里，我们描述了一种机制，即 ARF 肿瘤抑制因子与 PPM1G 结合，以负调控其在 NF-κB 回路中的共激活因子功能，从而促进损伤的解决。ARF 在与 PPM1G 结合后变得稳定，并以刺激依赖性方式与 PPM1G 和 NF-κB 在靶基因启动子上形成三元蛋白复合物，从而对 NF-κB 转录程序提供可调节的控制。一致地，在结肠上皮细胞中丢失 ARF 会导致在 TNF 刺激下 NF-κB 抗凋亡基因的上调，并使细胞在阻断抗凋亡程序的药物存在下对 TNF 诱导的凋亡部分耐药。值得注意的是，患者肿瘤数据分析通过揭示 的丢失与炎症和细胞存活程序的持续表达强烈相关，验证了这些发现。总的来说，我们提出 PPM1G 作为一种治疗靶点出现在由 ARF 表观遗传沉默、ARF 功能丧失以及携带致癌性 NF-κB 激活的各种癌症中。
