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Barrera Lawrence N. Ridley P. Matthew Bermejo-Rodriguez Camino Costello Eithne Perez-Mancera Pedro A. 《Journal of physiology and biochemistry》2023,79(1):193-204
Journal of Physiology and Biochemistry - Pancreatic ductal adenocarcinoma (PDAC) is the deadliest of the common cancers. A major hallmark of PDAC is an abundant and dense fibrotic stroma, the... 相似文献
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Kristina Kirschner Shamith A. Samarajiwa Jonathan M. Cairns Suraj Menon Pedro A. Pérez-Mancera Kosuke Tomimatsu Camino Bermejo-Rodriguez Yoko Ito Tamir Chandra Masako Narita Scott K. Lyons Andy G. Lynch Hiroshi Kimura Tetsuya Ohbayashi Simon Tavaré Masashi Narita 《PLoS genetics》2015,11(3)
The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical ‘acute’ p53 binding profile, ‘chronic’ p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory ‘p53 hubs’ where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the ‘lipogenic phenotype’, a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms. 相似文献
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