Dissecting the role of Gadd45b in hepatocellular carcinoma
Author
Rosato, UmbertoAdvisor
Salvador Sánchez, Jesús MaríaEntity
UAM. Departamento de Biología Molecular; CSIC. Centro Nacional de Biotecnología (CNB)Date
2017-04-21Subjects
Hígado - Cáncer - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 21-04-2017Esta tesis tiene embargado el acceso al texto completo hasta el 21-10-2018
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
The Gadd45 family proteins play a central role as stress sensors that modulate the
response of mammalian cells to stress inflicted by physiological and environmental
factors. Gadd45a and Gadd45b behave either as oncogenes or as tumor suppressor genes
in a cell-type dependent manner. Despite their role has been extensively studied in
various cancers, the functions played by these proteins in hepatocellular carcinoma
development remains unknown. We addressed this issue by studying HCC development
in a cohort of wild-types Gadd45a and Gadd45b null mice injected with
diethylnitrosamine (DEN) a hepatocarcinogenic agent. We show that loss of either
Gadd45a or Gadd45b strongly inhibits DEN-induced hepatocarcinogenesis. The lack of
Gadd45b or Gadd45a in mice decreased hepatocyte death and compensatory proliferation,
after DEN treatment. IL-6 is required for proliferation upon DEN-injection and the
decrease of IL-6 production in both Gadd45a and Gadd45b null mice was linked to a
decrease in JNK activation. Furthermore, we show that ablation of Gadd45b in Kupffer
cells, but not in hepatocytes, is sufficient to recapitulate the decrease in proliferation and
IL-6 production observed in whole body Gadd45b null mice. Altogether, these results
provide a novel role for both Gadd45b and Gadd45a as oncogenes during DEN-induced
HCC, and establish Gadd45b as critical player in regulating IL-6 production during liver
injury.
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