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Updated: Apr 27, 2026
Inducible and Reversible Dominant-negative DN Protein Inhibition
Published on: January 7, 2019
Organ size control is dominant over Rb family inactivation to restrict proliferation in vivo
Ursula Ehmer1, Anne-Flore Zmoos1, Raymond K Auerbach1
1Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
Abstract:
In mammals, a cell's decision to divide is thought to be under the control of the Rb/E2F pathway. We previously found that inactivation of the Rb family of cell cycle inhibitors (Rb, p107, and p130) in quiescent liver progenitors leads to uncontrolled division and cancer initiation. Here, we show that, in contrast, deletion of the entire Rb gene family in mature hepatocytes is not sufficient for their long-term proliferation. The cell cycle block in Rb family mutant hepatocytes is independent of the Arf/p53/p21 checkpoint but can be abrogated upon decreasing liver size. At the molecular level, we identify YAP, a transcriptional regulator involved in organ size control, as a factor required for the sustained expression of cell cycle genes in hepatocytes. These experiments identify a higher level of regulation of the cell cycle in vivo in which signals regulating organ size are dominant regulators of the core cell cycle machinery.
Insights
Inactivating the Rb gene family in mature liver cells doesn't cause uncontrolled division. Organ size signals, regulated by YAP, are crucial for sustained cell cycle progression in hepatocytes.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- The Retinoblastoma (Rb)/E2F pathway is a key regulator of cell division in mammals.
- Inactivation of Rb family proteins in liver progenitors causes uncontrolled proliferation and cancer.
- The role of Rb family proteins in mature hepatocytes remains less understood.
Purpose of the Study:
- To investigate the role of the Rb gene family in the proliferation of mature hepatocytes.
- To identify molecular mechanisms underlying cell cycle control in hepatocytes.
- To explore the interplay between organ size regulation and cell cycle machinery.
Main Methods:
- Genetic deletion of the entire Rb gene family (Rb, p107, p130) in mature mouse hepatocytes.
- Assessment of hepatocyte proliferation and cell cycle progression.
- Analysis of the Arf/p53/p21 checkpoint.
- Investigation of the role of YAP in cell cycle gene expression.
- Manipulation of liver size to study its effect on proliferation.
Main Results:
- Deletion of the Rb gene family in mature hepatocytes does not lead to sustained proliferation.
- The cell cycle block in Rb-deficient hepatocytes is independent of the Arf/p53/p21 pathway.
- Reducing liver size abrogates the cell cycle block in Rb family mutant hepatocytes.
- YAP, a transcriptional regulator of organ size, is essential for sustained cell cycle gene expression in hepatocytes.
Conclusions:
- Mature hepatocytes possess robust cell cycle checkpoints that prevent proliferation even after Rb family inactivation.
- Organ size regulatory signals, particularly those involving YAP, play a dominant role in controlling the core cell cycle machinery in vivo.
- These findings reveal a higher-order regulation of the cell cycle where organ size signals dictate proliferative capacity.
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