Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
E2f8 mediates tumor suppression in postnatal liver development
Lindsey N. Kent, … , Alain de Bruin, Gustavo Leone
Lindsey N. Kent, … , Alain de Bruin, Gustavo Leone
Published July 25, 2016
Citation Information: J Clin Invest. 2016;126(8):2955-2969. https://doi.org/10.1172/JCI85506.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 2

E2f8 mediates tumor suppression in postnatal liver development

  • Text
  • PDF
Abstract

E2F-mediated transcriptional repression of cell cycle–dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8’s tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8’s DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development.

Authors

Lindsey N. Kent, Jessica B. Rakijas, Shusil K. Pandit, Bart Westendorp, Hui-Zi Chen, Justin T. Huntington, Xing Tang, Sooin Bae, Arunima Srivastava, Shantibhusan Senapati, Christopher Koivisto, Chelsea K. Martin, Maria C. Cuitino, Miguel Perez, Julian M. Clouse, Veda Chokshi, Neelam Shinde, Raleigh Kladney, Daokun Sun, Antonio Perez-Castro, Ramadhan B. Matondo, Sathidpak Nantasanti, Michal Mokry, Kun Huang, Raghu Machiraju, Soledad Fernandez, Thomas J. Rosol, Vincenzo Coppola, Kamal S. Pohar, James M. Pipas, Carl R. Schmidt, Alain de Bruin, Gustavo Leone

×

Figure 4

DNA binding activity is required for E2F8 function during development.

Options: View larger image (or click on image) Download as PowerPoint
DNA binding activity is required for E2F8 function during development.
(...
(A) Diagram of the mouse E2f8 locus, targeting vector, and targeted E2f8 locus prior to and after germ line deletion of the neomycin (NEO) cassette using Sox2-Cre. A 5×MYC tag (red) was inserted after the ATG and the first DNA binding domain (DBD1) was mutated; amino acid changes are noted. Dashed lines show homologous recombination between targeting vector and endogenous locus. The purple line represents the Southern probe used to test embryonic stem (ES) cell clones after Sca1 digestion. (B) Sequencing histogram of wild-type (8+/+) and 8DBD/DBD mice showing the mutation in DBD1 of E2f8. Altered nucleotides and resulting amino acid changes are shown in red. (C) Southern blotting for the E2f8+ and E2f8DBD alleles in ES cells. (D) PCR genotyping of DNA from 8+/+, 8DBD/+, and 8DBD/DBD mice using primers flanking the LoxP site shown in A. The 8DBD (320 bp) and 8+ (209 bp) bands are noted. (E) ChIP-qPCR using IgG or MYC antibodies in HepG2 cells (control) or HepG2 cells expressing 5×MYC-tagged wild-type E2F8 (MYC-8wt) or 5×MYC-tagged DBD E2F8 (MYC-8DBD). CDC6 and MCM5 are established E2F targets; TUBA4A is shown as a negative control. Percentage of input values for MYC-tagged E2F8 were normalized to IgG. (F) Pictures of 8+/+ and 8DBD/DBD mice. (G) H&E-stained sections from E10.5 7–/– 8+/+ and 7–/– 8DBD/DBD placentation sites illustrating altered placental architecture with a disruption in fetal capillary formation and pooling of maternal blood in 7–/– 8DBD/DBD placentas. Arrows, fetal blood vessels. Arrowheads, maternal blood sinuses. Scale bars: 500 μm (left) and 50 μm (right). (H) Higher magnification of sections from G illustrating altered placental architecture with compaction of the placental junctional zone (JZ) and limited trophoblast invasion (arrowheads) in 7–/– 8DBD/DBD placentas. Scale bar: 500 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 2 X users
On 2 Facebook pages
59 readers on Mendeley
See more details