Liver-Specific pRB Loss Results in Ectopic Cell Cycle Entry and Aberrant Ploidy
Open accessAbstract
The liver exhibits an exquisitely controlled cell cycle, wherein hepatocytes are maintained in quiescence until stimulated to proliferate. The retinoblastoma tumor suppressor, pRB, plays a central role in proliferative control by inhibiting inappropriate cell cycle entry. In many cases, liver cancer arises due to aberrant cycles of proliferation, and correspondingly, pRB is functionally inactivated in the majority of hepatocellular carcinomas. Therefore, to determine how pRB loss may provide conditions permissive for deregulated hepatocyte proliferation, we investigated the consequence of somatic pRB inactivation in murine liver. We show that liver-specific pRB loss results in E2F target gene deregulation and elevated cell cycle progression during post-natal growth. However, in adult livers, E2F targets are repressed and hepatocytes become quiescent independent of pRB, suggesting that other factors may compensate for pRB loss. Therefore, to probe the consequences of acute pRB inactivation in livers of adult mice, we gave adenoviral-Cre by i.v. injection. We show that acute pRB loss is sufficient to elicit E2F target gene expression and cell cycle entry in adult liver, demonstrating a critical role for pRB in maintaining hepatocyte quiescence. Finally, we show that liver-specific pRB loss results in the development of nuclear pleomorphism associated with elevated ploidy that is evident in adult mice harboring both acute and chronic pRB loss. Together, these results show the crucial role played by pRB in maintaining hepatocyte quiescence and ploidy in adult liver in vivo and underscore the critical importance of delineating the consequences of acute pRB loss in adult animals.
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Loss of Rb results in cell cycle re-entry in mature hepatocytes.
“loss of Rb results in cell cycle re-entry in mature hepatocytes43.”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [43]
In normal adult hepatocytes, acute deletion of Rb results in cell cycle re-entry and increased aneuploidy.
“In normal adult hepatocytes, which are often tetraploid, acute deletion of Rb results in cell cycle re-entry and increased aneuploidy43.”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [43]
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- Authors
- Mayhew, C. N., Bosco, E. E., Fox, S. R., Okaya, T., Tarapore, P., Schwemberger, S. J., Babcock, G. F., Lentsch, A. B., Fukasawa, K., & Knudsen, E. S.
- Affiliations
- 1Cell Biology and Departments of
- 2Surgery, College of Medicine and
- University of Cincinnati (US)
- Venue
- Cancer Research
- Published
- 2005-06-01
- Volume
- 65
- Issue
- 11
- Pages
- 4568-4577
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2107840687
- Cited by
- 101
- References
- 68
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 6 · 2013: 3 · 2012: 7
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hennepin County Medical Center
- National Cancer Institute (CA-106471, T32-CA59268, R01CA106471, T32CA059268)
- National Institute of Environmental Health Sciences (E30-ES 06096)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- retinoblastoma protein, hepatocyte quiescence, cell cycle entry, E2F target genes, hepatocyte proliferation, nuclear pleomorphism, polyploidy, hepatocellular carcinoma, liver cancer
- MeSH terms
- Animals, Cell Cycle, DNA-Binding Proteins, Liver, Ploidies, Transcription Factors, Retinoblastoma Protein, Genes, Retinoblastoma, Mice, Knockout, Cell Cycle Proteins, Gene Silencing, Hepatocytes, Cell Growth Processes, E2F Transcription Factors, Mice
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