Abstract
The cellular signals that initiate cell growth are incompletely understood. Insight could be provided by understanding the signals regulating the transcriptional induction of immediate-early genes which occurs within minutes of the growth stimulus. The expression of the PRL-1 gene, which encodes a unique nuclear protein-tyrosine phosphatase, is rapidly induced in regenerating liver and mitogen-treated cells. Transcription of the PRL-1 gene increased in the rat liver remnant within a few minutes after partial hepatectomy and largely explained the increase in steady-state PRL-1 mRNA in the first few hours posthepatectomy. Egr-1 (early growth response factor) specifically bound a region of the proximal PRL-1 promoter P1 (-99). Egr-1 binding activity was more rapidly induced in regenerating liver than mitogen-treated H35 and NIH 3T3 cells, remained elevated through 4 h posthepatectomy, and appeared to be dependent not only on new Egr-1 protein synthesis but on post-translational regulation of Egr-1. Egr-1 efficiently transactivated a PRL-1 promoter reporter construct containing an intact not mutant Egr-1 site, and the Egr-1 site largely accounted for PRL-1 gene up-regulation in response to mitogen stimulation. These data predict that Egr-1 activation is an early event in liver regeneration and mitogen-activated cells that provides a regulatory stimulus for a subset of immediate-early genes.
Highlights
The cellular signals that initiate cell growth are incompletely understood
We showed that interleukin-6 (IL-6) which is increased in the liver posthepatectomy is required for normal liver regeneration [2]
Nuclear run-on assays indicated that phosphatase of regenerating liver-1 (PRL-1) gene transcription, which was virtually absent in normal liver, increased by 14.8-fold at 30 min posthepatectomy and remained elevated (10-fold) at 2 h posthepatectomy (Fig. 1B)
Summary
The cellular signals that initiate cell growth are incompletely understood. Insight could be provided by understanding the signals regulating the transcriptional induction of immediate-early genes which occurs within minutes of the growth stimulus. The expression of the PRL-1 gene, which encodes a unique nuclear protein-tyrosine phosphatase, is rapidly induced in regenerating liver and mitogen-treated cells. Egr-1 efficiently transactivated a PRL-1 promoter reporter construct containing an intact not mutant Egr-1 site, and the Egr-1 site largely accounted for PRL-1 gene up-regulation in response to mitogen stimulation These data predict that Egr-1 activation is an early event in liver regeneration and mitogen-activated cells that provides a regulatory stimulus for a subset of immediateearly genes. Following a partial hepatectomy or toxic liver injury, remnant liver cells that are normally quiescent rapidly reenter the cell cycle within minutes followed by DNA replication and restoration of liver mass within a few days The factors regulating this process are incompletely understood, but a number of growth factors and cellular signals have been implicated [1]. Egr-1 expression is rapidly and transiently induced during the transition of cells from the G0 to G1 phase in response to various mitogens such as growth factors, cytokines, injury, and partial hepatectomy.[7, 9, 13,14,15,16,17,18,19]
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