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Cell Rep. 2014 Jul 24;8(2):371-81. doi: 10.1016/j.celrep.2014.06.025. Epub 2014 Jul 10.

Organ size control is dominant over Rb family inactivation to restrict proliferation in vivo.

Author information

1
Department 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.
2
Department 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. Electronic address: julsage@stanford.edu.

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.

PMID:
25017070
PMCID:
PMC4128252
DOI:
10.1016/j.celrep.2014.06.025
[Indexed for MEDLINE]
Free PMC Article
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