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.
We have recently shown that overexpression of c-myc and transforming growth factor alpha (TGF-alpha) 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-alpha/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-alpha/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-alpha/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-alpha 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.
Factor
V M
VM
Laboratory of Experimental Carcinogenesis, DBS, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Jensen
M R
MR
Thorgeirsson
S S
SS
D000375:Aging; D000818:Animals; D015152:Blotting, Northern; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D004247:DNA / Q000032:analysis / Q000096:biosynthesis; D006498:Hepatectomy; D007150:Immunohistochemistry; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; D016271:Proto-Oncogene Proteins c-myc; D016211:Transforming Growth Factor alpha; D004247:DNA