Transient expression of cyclin D1 is sufficient to promote hepatocyte replication and liver growth in vivo

Cyclin D1 regulates mitogen-dependent progression through G(1) phase in cul tured cells, and its overexpression in malignant cells is thought to contri bute to autonomous proliferation in vivo. However, previous studies in cell lines have not demonstrated that cyclin D1 is sufficient to trigger cell r eplication. In this study, we found that transient transfection of adult he patocytes with cyclin D1 stimulated assembly of active cyclin D1/cdk4 compl exes, robust hepatocyte proliferation, and liver growth in the intact anima l. After several days, hepatocyte proliferation was inhibited despite the p ersistence of high levels of cyclin D1 and cyclin E, suggesting that endoge nous antiproliferative mechanisms were induced. Our data suggest that this antiproliferative response includes the marked up-regulation of p21, which in turn inhibits cyclin D1/cdk4 and cyclin E/cdk2 complexes. This study off ers further evidence that cyclin D1 plays a pivotal role in the regulation of hepatocyte proliferation in the liver. Furthermore, this model may offer a unique system to study the normal cellular response to cyclin D1 express ion in vivo.