title: A genetic screen identifies TCF3/E2A and TRIAP1 as pathway-specific regulators of the cellular response to p53 activation.
abstract: The p53 transcription factor participates in diverse cellular responses to stress, including cell-cycle arrest, apoptosis, senescence, and autophagy. The molecular mechanisms defining the ultimate outcome of p53 activation remain poorly characterized. We performed a genome-wide genetic screen in human cells to identify pathway-specific coregulators of the p53 target gene CDKN1A (p21), an inhibitor of cell-cycle progression, versus BBC3 (PUMA), a key mediator of apoptosis. Our screen identified numerous factors whose depletion creates an imbalance in the p21:PUMA ratio upon p53 activation. The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins. Accordingly, TCF3/E2A depletion impairs the cell-cycle-arrest response and promotes apoptosis upon p53 activation by chemotherapeutic agents. In contrast, TRIAP1 is a specific repressor of p21 whose depletion slows down cell-cycle progression. Our results reveal strategies for driving cells toward specific p53-dependent responses.
authors.affiliation: Howard Hughes Medical Institute & Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Andrysik
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Espinosa
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012319:RNA Polymerase II; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C438378:BBC3 protein, human; C118089:TFPT protein, human; C498536:TRIAP1 protein, human