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Sustained ERK signaling promotes G2 cell cycle exit and primes cells for whole-genome duplication.
Guerrero Zuniga, Adler; Aikin, Timothy J; McKenney, Connor; Lendner, Yovel; Phung, Alain; Hook, Paul W; Meltzer, Amy; Timp, Winston; Regot, Sergi.
Afiliación
  • Guerrero Zuniga A; Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular and Molecular Biology Graduate Program, The Johns Hop
  • Aikin TJ; Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular and Molecular Biology Graduate Program, The Johns Hop
  • McKenney C; Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular and Molecular Biology Graduate Program, The Johns Hop
  • Lendner Y; Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Phung A; Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Hook PW; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21205, USA.
  • Meltzer A; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21205, USA.
  • Timp W; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21205, USA.
  • Regot S; Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: sregot@jhmi.edu.
Dev Cell ; 59(13): 1724-1736.e4, 2024 Jul 08.
Article en En | MEDLINE | ID: mdl-38640927
ABSTRACT
Whole-genome duplication (WGD) is a frequent event in cancer evolution that fuels chromosomal instability. WGD can result from mitotic errors or endoreduplication, yet the molecular mechanisms that drive WGD remain unclear. Here, we use live single-cell analysis to characterize cell-cycle dynamics upon aberrant Ras-ERK signaling. We find that sustained ERK signaling in human cells leads to reactivation of the APC/C in G2, resulting in tetraploid G0-like cells that are primed for WGD. This process is independent of DNA damage or p53 but dependent on p21. Transcriptomics analysis and live-cell imaging showed that constitutive ERK activity promotes p21 expression, which is necessary and sufficient to inhibit CDK activity and which prematurely activates the anaphase-promoting complex (APC/C). Finally, either loss of p53 or reduced ERK signaling allowed for endoreduplication, completing a WGD event. Thus, sustained ERK signaling-induced G2 cell cycle exit represents an alternative path to WGD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína p53 Supresora de Tumor / Sistema de Señalización de MAP Quinasas Límite: Humans Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína p53 Supresora de Tumor / Sistema de Señalización de MAP Quinasas Límite: Humans Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos