The ability of the liver to regenerate after partial hepatectomy provides a unique system to study the in vivo regulation of cell proliferation and gene expression. The detailed nature of the controlling factors which regulate this phenomenon are only now beginning to surface and appear to represent a complex cascade of intracellular events. The unusual ability of the liver to regenerate is critical for its recovery from a number of disease states as well as surgical and chemical injury. It is solely dependent on the reentry of normally quiescent cells into an active state of cell division. The major objective of this proposal is to characterize the role of messenger RNA (mRNA) stability in the expression of certain cell-cycle dependent gene products in the regenerating rat liver. Our hypothesis is that the modulation of mRNA stability is predominately responsible for the expression of these transcripts during liver regeneration.
The specific aims of this proposal are, (1) to confirm that the increased mRNA expression of certain protooncogenes (c-fos, c-myc, c-jun, the ras gene family and p53) involved in cellular proliferation results from changes in stability rather than changes in transcriptional rate; (2) to isolate and characterize specific cytosolic factors which regulate the stability of these gene products; and (3) to establish an in vitro hepatocyte culture system to study that aspect of posttranscriptional modulation of gene expression. Our ultimate goal is to formulate a mechanistic model to explain the regulation of mRNA stability in the regenerating rat liver. In order to accomplish these aims, it will be necessary to apply techniques in both cell and molecular biology. Initial studies will determine the half-life of the protooncogene mRNAs in control and regenerating liver. Those results will be compared to the mRNA half-life of other cell-cycle dependent gene products, including ornithine decarboxylase and histone H4, as well as the liver-specific transcripts for albumin and the asialoglycoprotein receptor. Careful attention will be paid to the stability of the beta1 gap junction protein and P450IIE1 mRNAs, which in contrast to those noted above, significantly decrease during the inial phases of liver regeneration. The proposed studies will provide important insight into understanding the mechanisms involved in the regulation of normal cell growth in the liver as well as perhaps other tissues. More importantly, the results should shed light on potential mechanisms involved in the regulation of abnormal cell proliferation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044649-02
Application #
3246193
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1992-05-01
Project End
1995-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Kren, Betsy T; Wong, Phillip Y-P; Shiota, Akira et al. (2009) Polysome trafficking of transcripts and microRNAs in regenerating liver after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 297:G1181-92
Minuk, G Y; Kren, B T; Xu, R et al. (1997) The effect of changes in hepatocyte membrane potential on immediate-early proto-oncogene expression following partial hepatectomy in rats. Hepatology 25:1123-7
Kren, B T; Trembley, J H; Fan, G et al. (1997) Molecular regulation of liver regeneration. Ann N Y Acad Sci 831:361-81
Kren, B T; Steer, C J (1996) Posttranscriptional regulation of gene expression in liver regeneration: role of mRNA stability. FASEB J 10:559-73
Trembley, J H; Ebbert, J O; Kren, B T et al. (1996) Differential regulation of cyclin B1 RNA and protein expression during hepatocyte growth in vivo. Cell Growth Differ 7:903-16
Kren, B T; Trembley, J H; Krajewski, S et al. (1996) Modulation of apoptosis-associated genes bcl-2, bcl-x, and bax during rat liver regeneration. Cell Growth Differ 7:1633-42
Kren, B T; Trembley, J H; Steer, C J (1996) Alterations in mRNA stability during rat liver regeneration. Am J Physiol 270:G763-77
Kren, B T; Rodrigues, C M; Setchell, K D et al. (1995) Posttranscriptional regulation of mRNA levels in rat liver associated with deoxycholic acid feeding. Am J Physiol 269:G961-73
Trembley, J H; Kren, B T; Steer, C J (1994) Posttranscriptional regulation of cyclin B messenger RNA expression in the regenerating rat liver. Cell Growth Differ 5:99-108
Albrecht, J H; Muller-Eberhard, U; Kren, B T et al. (1994) Influence of transcriptional regulation and mRNA stability on hemopexin gene expression in regenerating liver. Arch Biochem Biophys 314:229-33

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