Analysis of the role of transcription factors NF-kappa B and Stat3 in the initiation of liver regeneration

Drew Edward Cressman, University of Pennsylvania

Abstract

The liver is one of the few organs in the body that retains the ability to regenerate following injury, infection, damage or surgical trauma. Following removal of 70% of the liver, normally quiescent cells in the remnant liver enter the cell cycle and begin to proliferate. Growth continues for 7 to 10 days until the original mass of the liver is restored. Within hours following partial hepatectomy, the expression of a number of genes is induced in the absence of additional protein synthesis. However, the transcription factors activated to mediate the initial changes in this immediate-early gene expression, the mechanisms by which these factors are regulated, and the signals involved in the initiation of liver regeneration remain poorly understood. In the work presented here, two transcription factors have been identified that are activated soon after partial hepatectomy, PHF/NF-$\kappa$B and Stat3. The modes of regulation, target genes, and the consequences of the loss of these transcription factors are examined in a regenerating liver system. One of the earliest changes in the remnant liver posthepatectomy is the activation of DNA binding of PHF/NF-$\kappa$B. Down-regulation of PHF/NF-$\kappa$B occurs through proteolytic degradation of its p65/RelA subunit, along with release of DNA-bound PHF/NF-$\kappa$B mediated by the influx of newly synthesized $\rm I\kappa B\alpha,$ an inhibitor of PHF/NF-$\kappa$B. Mice deficient for the p50 subunit of PHF/NF-$\kappa$B show moderate effects on hepatocyte proliferation and target gene expression, as well as decreased Stat3 activation. The Stat3 transcription factor displays peak DNA binding activity at 2-3 h posthepatectomy. The interleukin-6 cytokine is capable of strongly activating Stat3, while posthepatectomy Stat3 binding is eliminated in mice deficient for IL-6. Loss of Stat3 binding correlates with decreased target gene expression and diminished and delayed hepatocyte proliferation following partial hepatectomy in IL-6 knockout animals. These findings define a critical role for IL-6 as a stimulating signal and PHF/NF-$\kappa$B and Stat3 as early transcription factors necessary for the initiation of liver regeneration.

Subject Area

Molecular biology|Surgery|Cellular biology

Recommended Citation

Cressman, Drew Edward, "Analysis of the role of transcription factors NF-kappa B and Stat3 in the initiation of liver regeneration" (1996). Dissertations available from ProQuest. AAI9627907.
https://repository.upenn.edu/dissertations/AAI9627907

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