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Molecular and Cellular Biology, February 2003, p. 1251-1259, Vol. 23, No. 4
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.4.1251-1259.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Impaired Hepatocyte DNA Synthetic Response Posthepatectomy in Insulin-Like Growth Factor Binding Protein 1-Deficient Mice with Defects in C/EBPß and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Regulation

Julia I. Leu,1 Mary Ann S. Crissey,1,{dagger} Linden E. Craig,2,{ddagger} and Rebecca Taub1*

Department of Genetics, University of Pennsylvania School of Medicine,1 Laboratory of Pathology and Toxicology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 191042

Received 14 May 2002/ Returned for modification 20 July 2002/ Accepted 12 November 2002

After a two-thirds hepatectomy, normally quiescent liver cells are stimulated to reenter the cell cycle and proliferate to restore the original liver mass. One of the most rapidly and highly induced genes and proteins in regenerating liver is insulin-like growth factor binding protein 1 (IGFBP-1), a secreted protein that may modulate the activities of insulin-like growth factors (IGFs) or signal via IGF-independent mechanisms. To assess the functional role of IGFBP-1 in liver regeneration, mice with a targeted disruption of the IGFBP-1 gene were generated. Although IGFBP-1-/- mice demonstrated normal development, they had abnormal liver regeneration after partial hepatectomy, characterized by liver necrosis and reduced and delayed hepatocyte DNA synthesis. The abnormal regenerative response was associated with blunted activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and a reduced induction of C/EBPß protein expression posthepatectomy. Like cell cycle abnormalities observed in hepatectomized C/EBPß-/- mice, cyclin A and cyclin B1 expression was delayed and reduced in IGFBP-1-/- livers, whereas cyclin D1 expression was normal. Treatment of IGFBP-1-/- mice with a preoperative dose of IGFBP-1 induced MAPK/ERK activation and C/EBPß expression, suggesting that IGFBP-1 may support liver regeneration at least in part via its effect on MAPK/ERK and C/EBPß activities. These findings are the first demonstration of the involvement of IGFBP-1 in the regulation of in vivo mitogenic signaling pathways.

* Corresponding author. Present address: Bristol Myers Squibb, Mail Stop 3CD-468, 5 Research Pkwy., Wallingford, CT 06492. Phone: (203) 677-6727. Fax: (203) 677-7569. E-mail: rebecca.taub{at}bms.com.

{dagger} Present address: Bristol Myers Squibb, Wilmington, DE 19880-0400.

{ddagger} Present address: Department of Pathobiology, University of Tennessee College of Veterinary Medicine, Knoxville, TN 37996-4500.

Molecular and Cellular Biology, February 2003, p. 1251-1259, Vol. 23, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.4.1251-1259.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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