KLF5 and p53 comprise an incoherent feed-forward loop directing cell-fate decisions following stress.

Autor: Yang Y; Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA., Bhargava D; Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA., Chen X; Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA., Zhou T; Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA., Dursuk G; Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA., Jiang W; Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA., Wang J; Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA., Zong Z; Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA., Katz SI; Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA., Lomberk GA; Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Urrutia RA; Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.; Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Katz JP; Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. jpkatz@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2023 May 02; Vol. 14 (5), pp. 299. Date of Electronic Publication: 2023 May 02.
DOI: 10.1038/s41419-023-05731-1
Abstrakt: In response to stress, cells make a critical decision to arrest or undergo apoptosis, mediated in large part by the tumor suppressor p53. Yet the mechanisms of these cell fate decisions remain largely unknown, particularly in normal cells. Here, we define an incoherent feed-forward loop in non-transformed human squamous epithelial cells involving p53 and the zinc-finger transcription factor KLF5 that dictates responses to differing levels of cellular stress from UV irradiation or oxidative stress. In normal unstressed human squamous epithelial cells, KLF5 complexes with SIN3A and HDAC2 repress TP53, allowing cells to proliferate. With moderate stress, this complex is disrupted, and TP53 is induced; KLF5 then acts as a molecular switch for p53 function by transactivating AKT1 and AKT3, which direct cells toward survival. By contrast, severe stress results in KLF5 loss, such that AKT1 and AKT3 are not induced, and cells preferentially undergo apoptosis. Thus, in human squamous epithelial cells, KLF5 gates the response to UV or oxidative stress to determine the p53 output of growth arrest or apoptosis.
(© 2023. The Author(s).)
Databáze: MEDLINE
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