Co-inhibition of ATM and ROCK synergistically improves cell proliferation in replicative senescence by activating FOXM1 and E2F1 View Full Text


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Article Info

DATE

2022-07-14

AUTHORS

Eun Jae Yang, Ji Hwan Park, Hyun-Ji Cho, Jeong-A Hwang, Seung-Hwa Woo, Chi Hyun Park, Sung Young Kim, Joon Tae Park, Sang Chul Park, Daehee Hwang, Young-Sam Lee

ABSTRACT

The multifaceted nature of senescent cell cycle arrest necessitates the targeting of multiple factors arresting or promoting the cell cycle. We report that co-inhibition of ATM and ROCK by KU-60019 and Y-27632, respectively, synergistically increases the proliferation of human diploid fibroblasts undergoing replicative senescence through activation of the transcription factors E2F1 and FOXM1. Time-course transcriptome analysis identified FOXM1 and E2F1 as crucial factors promoting proliferation. Co-inhibition of the kinases ATM and ROCK first promotes the G2/M transition via FOXM1 activation, leading to accumulation of cells undergoing the G1/S transition via E2F1 activation. The combination of both inhibitors increased this effect more significantly than either inhibitor alone, suggesting synergism. Our results demonstrate a FOXM1- and E2F1-mediated molecular pathway enhancing cell cycle progression in cells with proliferative potential under replicative senescence conditions, and treatment with the inhibitors can be tested for senomorphic effect in vivo. More... »

PAGES

702

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s42003-022-03658-5

    DOI

    http://dx.doi.org/10.1038/s42003-022-03658-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1149463795

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/35835838


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