Faculty Collaboration Database

KLF5 and p53 comprise an incoherent feed-forward loop directing cell-fate decisions following stress. Cell Death Dis 2023 May 02;14(5):299

Date

05/03/2023

Pubmed ID

37130837

Pubmed Central ID

PMC10154356

DOI

10.1038/s41419-023-05731-1

Scopus ID

2-s2.0-85157983058 (requires institutional sign-in at Scopus site)

Abstract

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.

Author List

Yang Y, Bhargava D, Chen X, Zhou T, Dursuk G, Jiang W, Wang J, Zong Z, Katz SI, Lomberk GA, Urrutia RA, Katz JP

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Apoptosis
Cell Differentiation
Epithelial Cells
Humans
Kruppel-Like Transcription Factors
Oxidative Stress
Tumor Suppressor Protein p53