The ARF tumor suppressor targets PPM1G/PP2Cgamma to counteract NF-kappaB transcription tuning cell survival and the inflammatory response

Menée à l'aide de lignées de cellules cancéreuses, cette étude met en évidence un mécanisme par lequel le suppresseur de tumeur ARF, en ciblant les phosphatases PPM1G/PP2Cgamma, inhibe la fonction transcriptionnelle du facteur NF-kappa

Résumé en anglais

The NF-κB signaling pathway is critical for cellular responses to cell-extrinsic insults. Its dysregulation impacts cancer patients’ survival and response to available therapeutics. NF-κB utilizes the PPM1G phosphatase as a coactivator to induce inflammatory and cell survival programs in response to proinflammatory cytokines. However, how PPM1G activity is regulated to facilitate tunable control and insult resolution remains enigmatic. We take advantage of biochemical and genetic approaches and patient tumor data analysis to reveal a key function of the p14ARF tumor suppressor in targeting PPM1G to negatively tune NF-κB transcriptional function, thereby controlling inflammatory and apoptotic responses. We propose that PPM1G emerges as a therapeutic target in a variety of cancers arising from ARF loss of function to oncogenic NF-κB activation.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 ARF 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.All study data are included in the article and supporting information.