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 g rowth 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-tr ansgenic mice. We now report that double-transgenic TGF-alpha/c-myc he patocytes rapidly lose their ability to proliferate upon mitogenic sti mulation following partial hepatectomy (PH). At 4 weeks of age, the ov erall 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-tran sgenic 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 pro liferative response was accompanied by a reduction in the total fracti on of proliferating hepatocytes, as well as by a decline in the induct ion of cyclin A, cyclin B, and cdc2 gene expression, These data show t hat constitutive coexpression of c-myc and TGF-alpha accelerates age-r elated loss in the regenerative potential following PH, and suggest th at early replicative senescence of differentiated hepatocytes may have a role in providing a selective growth advantage to initiated cell po pulations in this model.