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Coexpression of C‐myc and transforming growth factor alfa in the liver promotes early replicative senescence and diminishes regenerative capacity after partial hepatectomy in transgenic mice

Coexpression of C‐myc and transforming growth factor alfa in the liver promotes early replicative... We have recently shown that overexpression of c‐myc and transforming growth factor α (TGF‐α) in the liver of double‐transgenic mice results in severe DNA damage, aberrant hepatic growth, and development of tumors at a much younger age than that observed in c‐myc single‐ transgenic mice. We now report that double‐transgenic TGF‐α/c‐myc hepatocytes rapidly lose their ability to proliferate upon mitogenic stimulation following partial hepatectomy (PH). At 4 weeks of age, the overall rate of bromodeoxyuridine (BrdU) incorporation following PH was comparable in c‐myc and TGF‐α/c‐myc livers and exceeded that seen in wild‐type (WT) mice. However, by 10 weeks of age, c‐myc single‐ transgenic hepatocytes showed proliferative advantages over the WT cells, whereas TGF‐α/c‐myc double‐transgenic hepatocytes had a decreased capacity to proliferate upon mitogenic stimulation. This decreased proliferative response was accompanied by a reduction in the total fraction of proliferating hepatocytes, as well as by a decline in the induction of cyclin A, cyclin B, and cdc2 gene expression. These data show that constitutive coexpression of c‐myc and TGF‐α accelerates age‐related loss in the regenerative potential following PH, and suggest that early replicative senescence of differentiated hepatocytes may have a role in providing a selective growth advantage to initiated cell populations in this model. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Hepatology Wolters Kluwer Health

Coexpression of C‐myc and transforming growth factor alfa in the liver promotes early replicative senescence and diminishes regenerative capacity after partial hepatectomy in transgenic mice

Factor, V M; Jensen, M R; Thorgeirsson, S S
Hepatology , Volume 26 (6) – Jan 1, 1997
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Coexpression of C‐myc and transforming growth factor alfa in the liver promotes early replicative senescence and diminishes regenerative capacity after partial hepatectomy in transgenic mice

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References (152)

Publisher
Wolters Kluwer Health
Copyright
Copyright © 1997 Wiley Subscription Services
ISSN
0270-9139
eISSN
1527-3350
DOI
10.1002/hep.510260610
pmid
9397983
Publisher site
See Article on Publisher Site

Abstract

We have recently shown that overexpression of c‐myc and transforming growth factor α (TGF‐α) in the liver of double‐transgenic mice results in severe DNA damage, aberrant hepatic growth, and development of tumors at a much younger age than that observed in c‐myc single‐ transgenic mice. We now report that double‐transgenic TGF‐α/c‐myc hepatocytes rapidly lose their ability to proliferate upon mitogenic stimulation following partial hepatectomy (PH). At 4 weeks of age, the overall rate of bromodeoxyuridine (BrdU) incorporation following PH was comparable in c‐myc and TGF‐α/c‐myc livers and exceeded that seen in wild‐type (WT) mice. However, by 10 weeks of age, c‐myc single‐ transgenic hepatocytes showed proliferative advantages over the WT cells, whereas TGF‐α/c‐myc double‐transgenic hepatocytes had a decreased capacity to proliferate upon mitogenic stimulation. This decreased proliferative response was accompanied by a reduction in the total fraction of proliferating hepatocytes, as well as by a decline in the induction of cyclin A, cyclin B, and cdc2 gene expression. These data show that constitutive coexpression of c‐myc and TGF‐α accelerates age‐related loss in the regenerative potential following PH, and suggest that early replicative senescence of differentiated hepatocytes may have a role in providing a selective growth advantage to initiated cell populations in this model.

Journal

Hepatology – Wolters Kluwer Health

Published: Jan 1, 1997

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