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Molecular and Cellular Biology, September 2001, p. 5723-5732, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5723-5732.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

HMG Box Transcriptional Repressor HBP1 Maintains a Proliferation Barrier in Differentiated Liver Tissue

Heather H. Shih,1,dagger Mei Xiu,1,2 Stephen P. Berasi,1 Ellen M. Sampson,1 Andrew Leiter,3 K. Eric Paulson,1,2 and Amy S. Yee1,*

Division of Gastroenterology, Department of Medicine, New England Medical Center,3 and Department of Biochemistry, Tufts University School of Medicine,1 and School of Nutrition, Tufts University,2 Boston, Massachusetts 02111

Received 12 June 2001/Accepted 15 June 2001

We previously isolated HBP1 as a target of the retinoblastoma (RB) and p130 family members and as the first of the HMG box transcriptional repressors. Our subsequent work demonstrated that HBP1 coordinates differentiation in cell culture models. In the present study, we show that HBP1 regulates proliferation in a differentiated tissue of an animal. Using transgenic mice in which HBP1 expression was specifically increased in hepatocytes under control of the transthyretin promoter, we determined the impact of HBP1 on synchronous cell cycle reentry following partial hepatectomy. Modest overexpression of HBP1 yielded a detectable cell cycle phenotype. Following a mitogenic stimulus induced by two-thirds partial hepatectomy, mice expressing the HBP1 transgene showed a 10- to 12-h delay in progression through G1 to the peak of S phase. There was a concomitant delay in mid-G1 events, such as the induction of cyclin E. While the delay in G1 and S phases correlated with the slight overexpression of transgenic HBP1, the level of the endogenous HBP1 protein itself declined in S phase. In contrast, the onset of the immediate-early response following partial hepatectomy was unchanged in HBP1 transgenic mice. This observation indicated that the observed delay in S phase did not result from changes in signaling pathways leading into the G0-to-G1 transition. Finally, transgenic mice expressing a mutant HBP1 lacking the N-terminal RB interacting domain showed a stronger S-phase response following partial hepatectomy. These results provide the first evidence that HBP1 can regulate cell cycle progression in differentiated tissues.

* Corresponding author. Mailing address: Department of Biochemistry, MV 612, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. Phone: (617) 636-6850. Fax: (617) 636-2409. E-mail: amy.yee{at}tufts.edu.

dagger Present address: Genetics Institute, Cambridge, Mass.

Molecular and Cellular Biology, September 2001, p. 5723-5732, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5723-5732.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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