Targeted in vivo expression of the cyclin-dependent kinase inhibitor p21 halts hepatocyte cell-cycle progression, postnatal liver development and regeneration.
The CDK inhibitor p21 (WAF-1/CIP-1/SDI-1) has been implicated in DNA damage-induced p53-mediated G1 arrest, as well as in physiological processes, such as cell differentiation and senescence, that do not involve p53 function. To determine the impact of p21 on normal development and cell-cycle regulation in vivo, we have generated transgenic mice that abundantly express p21 specifically in hepatocytes. During postnatal liver development, when transgenic p-21 protein becomes detectable, hepatocyte proliferation is inhibited dramatically. This disturbance causes a reduction in the overall number of adult hepatocytes, resulting in aberrant tissue organization, runted liver and body growth, and increased mortality. The transgenic p21 protein is associated with most, if not all, of the cyclin D1-CDK4 in liver but not significantly with other cyclin/CDK proteins, indicating the importance of cyclin D1-CDK4 function in normal liver development. The appearance of large polyploid nuclei in some hepatocytes indicates that p21 may also cause arrest during the G2 phase of the cell cycle. Significantly, partial hepatectomy failed to stimulate hepatocytes to proliferate in p21 transgenic animals. These results provide the first in vivo evidence that appropriate p21 levels are critical in normal development and further implicate p21 in the control of multiple cell-cycle phases.
Wu
H
H
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, 27599 USA.
Wade
M
M
Krall
L
L
Grisham
J
J
Xiong
Y
Y
Van Dyke
T
T
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000378:metabolism; D018390:Gene Targeting; D006498:Hepatectomy; D008099:Liver / Q000166:cytology* / Q000254:growth & development*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism; D011228:Prealbumin / Q000235:genetics; D011518:Proto-Oncogene Proteins
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D015513:Oncogene Proteins; D011228:Prealbumin; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D004247:DNA; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases