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

Ursula Ehmer; Anne-Flore Zmoos; Raymond K Auerbach; Dedeepya Vaka; Atul J Butte; Mark A Kay; Julien Sage

doi:10.1016/j.celrep.2014.06.025

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

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

Authors

Ursula Ehmer¹, Anne-Flore Zmoos¹, Raymond K Auerbach¹, Dedeepya Vaka¹, Atul J Butte¹, Mark A Kay¹, Julien Sage²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ADP-Ribosylation Factors / metabolism
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Cell Cycle Proteins
Cell Proliferation*
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Genes, cdc
Hepatocytes / cytology
Hepatocytes / metabolism
Hepatocytes / physiology
Liver / growth & development*
Liver / metabolism
Mice
Organ Size
Phosphoproteins / genetics
Phosphoproteins / metabolism
Retinoblastoma-Like Protein p107 / genetics
Retinoblastoma-Like Protein p107 / metabolism*
Retinoblastoma-Like Protein p130 / genetics
Retinoblastoma-Like Protein p130 / metabolism*
Tumor Suppressor Protein p53 / metabolism
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p21
Phosphoproteins
Rbl1 protein, mouse
Rbl2 protein, mouse
Retinoblastoma-Like Protein p107
Retinoblastoma-Like Protein p130
Tumor Suppressor Protein p53
YAP-Signaling Proteins
Yap1 protein, mouse
ADP-Ribosylation Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding