Similar Datasets
Project description:Immune cells identify and destroy damaged cells to prevent them from causing cancer or other pathologies by mechanisms that remain poorly understood. Here, we report that the cell-cycle inhibitor p21 places cells under immunosurveillance to establish a biological timer mechanism that controls cell fate. p21 activates retinoblastoma protein (Rb)–dependent transcription at select gene promoters to generate a complex bioactive secretome, termed p21-activated secretory phenotype (PASP). The PASP includes the chemokine CXCL14, which promptly attracts macrophages. These macrophages disengage if cells normalize p21 within 4 days, but if p21 induction persists, they polarize toward an M1 phenotype and lymphocytes mount a cytotoxic T cell response to eliminate target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress.
| S-EPMC8985214 | biostudies-literature
Project description:In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb.
2021-10-29 | GSE118605 | GEO
Project description:In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb.
2021-10-29 | GSE118584 | GEO
Project description:In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb.
2021-10-29 | GSE118583 | GEO
Project description:In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb.
2021-10-29 | GSE117979 | GEO
Project description:In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb.
2021-10-29 | GSE117276 | GEO
Project description:In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb.
2021-10-29 | GSE117147 | GEO
Project description:p21 produces a bioactive secretome that places stressed cells under immuno-surveillance.
2021-10-29 | GSE169329 | GEO
Project description:p21 produces a bioactive secretome that places stressed cells under immuno-surveillance
2021-10-29 | GSE169327 | GEO
Project description:In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb.
2021-10-29 | GSE139569 | GEO