Delayed Hepatocellular Mitotic Progression and Impaired Liver Regeneration in Early Growth Response-1-deficient Mice

Abstract

The early growth response-1 transcription factor (Egr-1) is induced as part of the immediate-early gene expression response during early liver regeneration. In the studies reported here the functional significance of EGR-1 expression during liver regeneration was examined by characterizing the hepatic regenerative response to partial hepatectomy in Egr-1 null mice. The results of these studies showed that liver regeneration in Egr-1 null mice is impaired. Although activation of interleukin-6-STAT3 signaling, regulation of expression of hepatic C/ebpα, C/ebpβ, cyclin D, and cyclin E and progression through the first wave of hepatocellular DNA synthesis occurred appropriately following partial hepatectomy in Egr-1 null mice, subsequent signaling events and cell cycle progression after the first round of DNA synthesis were deranged. This derangement was characterized by increased activation of the p38 mitogen-activated protein kinase and inhibition of hepatocellular metaphase-to-anaphase mitotic progression. Together these observations suggest that EGR-1 is an important regulator of hepatocellular mitotic progression. In support of this, microarray-based gene expression analysis showed that induction of expression of the cell division cycle 20 gene (Cdc20), a key regulator of the mitotic anaphase-promoting complex, is significantly reduced in Egr-1 null mice. Taken together these data define a novel functional role for EGR-1 in regulating hepatocellular mitotic progression through the spindle assembly checkpoint during liver regeneration. The early growth response-1 transcription factor (Egr-1) is induced as part of the immediate-early gene expression response during early liver regeneration. In the studies reported here the functional significance of EGR-1 expression during liver regeneration was examined by characterizing the hepatic regenerative response to partial hepatectomy in Egr-1 null mice. The results of these studies showed that liver regeneration in Egr-1 null mice is impaired. Although activation of interleukin-6-STAT3 signaling, regulation of expression of hepatic C/ebpα, C/ebpβ, cyclin D, and cyclin E and progression through the first wave of hepatocellular DNA synthesis occurred appropriately following partial hepatectomy in Egr-1 null mice, subsequent signaling events and cell cycle progression after the first round of DNA synthesis were deranged. This derangement was characterized by increased activation of the p38 mitogen-activated protein kinase and inhibition of hepatocellular metaphase-to-anaphase mitotic progression. Together these observations suggest that EGR-1 is an important regulator of hepatocellular mitotic progression. In support of this, microarray-based gene expression analysis showed that induction of expression of the cell division cycle 20 gene (Cdc20), a key regulator of the mitotic anaphase-promoting complex, is significantly reduced in Egr-1 null mice. Taken together these data define a novel functional role for EGR-1 in regulating hepatocellular mitotic progression through the spindle assembly checkpoint during liver regeneration. The liver regenerates in response to many forms of injury (1Fausto N. J. Hepatol. 2000; 32: 19-31Abstract Full Text PDF PubMed Google Scholar, 2Diehl A.M. Rai R. Schiff E.R. Sorrell M.F. Maddrey W.C. Schiff's Diseases of the Liver. Lippincott-Raven, Philadelphia1999: 39-54Google Scholar, 3Michalopoulos G.K. DeFrances M.C. Science. 1997; 276: 60-66Crossref PubMed Scopus (2870) Google Scholar). Liver regeneration is important for recovery from the functional hepatic deficits induced by such injuries and for host health and viability. Following injury, hepatic regeneration is precisely regulated in its initiation and proceeds only until the original liver mass is restored. This process does not depend upon a stem cell population; rather, all of the normally quiescent mature cellular populations of the liver have the potential to re-enter the cell cycle and proliferate. Hepatocytes are the first to replicate, followed sequentially by biliary epithelial, Kupffer, stellate, and sinusoidal endothelial cells (3Michalopoulos G.K. DeFrances M.C. Science. 1997; 276: 60-66Crossref PubMed Scopus (2870) Google Scholar). Normal liver architecture, distorted during the regenerative response, is then restored. Regeneration continues until normal hepatic function, mass, and structure are restored, and then it is precisely terminated as hepatocytes re-enter their pre-replicative state of quiescence. Although some aspects of the molecular machinery that control this carefully orchestrated response to injury are now known, many of the mechanisms involved in regulating liver regeneration remain incompletely understood. Elucidation of these signaling pathways in greater detail offers the potential to increase our understanding of the hepatic regenerative response in acute and chronic liver diseases, and may ultimately lead to novel therapeutic strategies for enhancing liver regeneration after hepatic injury. Furthermore, such studies could provide a paradigm for analyses of tissue regeneration in other organ systems. Partial hepatectomy has been an important model system for investigating the molecular signaling pathways that regulate the hepatic regenerative response (4Higgins G.M. Anderson R.M. Arch. Pathol. 1931; 12: 186-202Google Scholar). Analyses using this model show that activation of the tumor necrosis factor-α-IL-6 1The abbreviations used are: IL-6, interleukin-6; Egr-1, the early growth response 1 gene; EGR-1, the early growth response 1 protein; MAP, mitogen-activated protein kinase; Cdc20, cell division cycle 20 gene; ES cells, embryonic stem cells; BrdUrd, bromodeoxyuridine; Prl-1, the phosphatase of regenerating liver 1 gene; RT, reverse transcriptase; APC, anaphase-promoting complex; STAT, signal transducers and activators of transcription; ELISA, enzyme-linked immunosorbent assay; C/EBP, CCAAT/enhancer-binding protein. 1The abbreviations used are: IL-6, interleukin-6; Egr-1, the early growth response 1 gene; EGR-1, the early growth response 1 protein; MAP, mitogen-activated protein kinase; Cdc20, cell division cycle 20 gene; ES cells, embryonic stem cells; BrdUrd, bromodeoxyuridine; Prl-1, the phosphatase of regenerating liver 1 gene; RT, reverse transcriptase; APC, anaphase-promoting complex; STAT, signal transducers and activators of transcription; ELISA, enzyme-linked immunosorbent assay; C/EBP, CCAAT/enhancer-binding protein.-STAT3 cytokine signaling cascade is required for initiation of liver regeneration (5Akerman P. Cote P. Yang S.Q. McClain C. Nelson S. Bagby G.J. Diehl A.M. Am. J. Physiol. 1992; 263: G579-G585Crossref PubMed Google Scholar, 6Yamada Y. Kirillova I. Peschon J.J. Fausto N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1441-1446Crossref PubMed Scopus (828) Google Scholar, 7Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Crossref PubMed Scopus (1305) Google Scholar). This is followed by the coordinated generation of mitochondrial reactive oxygen species (8Lee F.Y. Li Y. Zhu H. Yang S. Lin H.Z. Trush M. Diehl A.M. Hepatology. 1999; 29: 677-687Crossref PubMed Scopus (144) Google Scholar) and prostaglandins (9Rudnick D.A. Perlmutter D.H. Muglia L.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8885-8890Crossref PubMed Scopus (125) Google Scholar), the activation of stress- and mitogen-activated-protein kinase cascades (10Talarmin H. Rescan C. Cariou S. Glaise D. Zanninelli G. Bilodeau M. Loyer P. Guguen-Guillouzo C. Baffet G. Mol. Cell. Biol. 1999; 19: 6003-6011Crossref PubMed Scopus (229) Google Scholar), as well as specific transcription factors including NFκb, AP-1, STAT3, cAMP-response element-binding protein (9Rudnick D.A. Perlmutter D.H. Muglia L.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8885-8890Crossref PubMed Scopus (125) Google Scholar), and others (11Cressman D.E. Greenbaum L.E. Haber B.A. Taub R. J. Biol. Chem. 1994; 269: 30429-30435Abstract Full Text PDF PubMed Google Scholar, 12Cressman D.E. Diamond R.H. Taub R. Hepatology. 1995; 21: 1443-1449Crossref PubMed Google Scholar, 13Taub R. FASEB J. 1996; 10: 413-427Crossref PubMed Scopus (319) Google Scholar). These events initiate an immediate-early gene expression program that includes increased expression of transcription including the protein L.E. Li D.E. Y. Ciliberto G. Poli V. Taub R. J. PubMed Scopus Google EGR-1 B.A. Diamond R.H. Taub R. J. PubMed Scopus Google Scholar), G. P. 1997; PubMed Scopus Google Scholar) and other growth hepatocellular and progression through the cell cycle (1Fausto N. J. Hepatol. 2000; 32: 19-31Abstract Full Text PDF PubMed Google Scholar). EGR-1, is as and is a transcription factor induced as part of the immediate-early gene expression program in the regenerating liver B.A. Diamond R.H. Taub R. J. PubMed Scopus Google Scholar, Y. S. Diamond R.H. Taub R. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). EGR-1 was first its induction in cells in response to growth factor J. Science. PubMed Scopus Google Scholar). studies have that EGR-1 expression is induced in a of of cellular during the from to and in of cellular D. Cell. Full Text PDF PubMed Scopus Google Scholar, B.A. D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, P. R. P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, Google the specific functional role of EGR-1 in these has not been In analyses of embryonic stem cells that EGR-1 is not required for ES cell and Egr-1 null mice a normal growth and in cellular J. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. P. G. J. Science. 1996; PubMed Scopus Google Scholar). In to EGR-1 expression is required for normal liver the response of Egr-1 null mice to partial hepatectomy was The results of these analyses showed that EGR-1 is an hepatic regenerative response that is characterized by hepatocellular progression through the mitotic spindle assembly These data provide for a novel functional role for EGR-1 in hepatocellular mitotic progression during liver regeneration. null mice were from a by of The of these mice has been Y. P. G. J. Science. 1996; PubMed Scopus Google Scholar). were used as were and a of and and after were by the of and in and the in the for and of of null and mice were to partial hepatectomy as (4Higgins G.M. Anderson R.M. Arch. Pathol. 1931; 12: 186-202Google Scholar, D.A. Perlmutter D.H. Muglia L.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8885-8890Crossref PubMed Scopus (125) Google Scholar). were and of and were to their to and after the were and their were for of hepatocellular for for gene expression analyses cellular generation for strategies were for analyses of hepatocellular In the were the of all hepatocytes that the of the this the a of of 1 20 were the of the In the were 1 after partial only hepatocytes that were the of tissue was for in and for of liver were and and for of hepatocellular the tissue the of hepatocellular as well as mitotic was by of and cells and were as for the of was by as (9Rudnick D.A. Perlmutter D.H. Muglia L.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8885-8890Crossref PubMed Scopus (125) Google Scholar). cell were from liver as (9Rudnick D.A. Perlmutter D.H. Muglia L.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8885-8890Crossref PubMed Scopus (125) Google Scholar). was using the protein of cellular protein was to followed by to were STAT3, followed by a and then using the system analysis was data analysis was from liver tissue using followed by using the was by and by expression of C/ebpα, C/ebpβ, cyclin D, cyclin Egr-1, Prl-1, and was by using these as from and Egr-1 null liver after partial was to by the gene an of was to a and reverse and reverse C/ebpβ, and reverse cyclin D, and reverse cyclin and reverse Egr-1, and reverse Prl-1, and reverse and reverse and of was increased during in a and of the cycle the a These data were to the expression of a used as a in analyses of gene expression during hepatic regeneration B.A. Diamond R.H. Taub R. J. PubMed Scopus Google Scholar), and the data were used to in gene expression of this was for gene by of and using and of the was by analysis of a all reverse hepatic was from regenerating Egr-1 null after partial hepatectomy as of from were and of this was to the Diseases of for microarray-based gene expression of the Egr-1 null were using the to the These were and to the G.J. S. Y. Y. R. H. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar), after the and was and to the and to the the were by the The data were to signal and an for the analyses gene expression data were to The data was by of expression a of in were the expression in the liver was that in Egr-1 null and that were induced were These were that have a of in gene expression that by other of A. and were using of for was used to significance for mitotic gene and are reported as was used to during Liver Regeneration in Egr-1 to EGR-1 expression is required for normal liver the hepatic regenerative response to partial hepatectomy in and Egr-1 null mice was mice were to partial hepatectomy and a the of The were to then and their and after These for analysis were to of this first wave of hepatocellular DNA synthesis and of the of hepatocellular DNA synthesis during hepatic regeneration following partial hepatectomy (9Rudnick D.A. Perlmutter D.H. Muglia L.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8885-8890Crossref PubMed Scopus (125) Google Scholar). Liver tissue was for hepatocellular this an of hepatocellular the of the The data from this analysis showed that is hepatocellular in and Egr-1 null mice after partial hepatectomy that progression through the first wave of hepatocellular DNA synthesis is not significantly in Egr-1 null mice and of liver after partial hepatectomy showed that hepatocellular continues to increase from to in mice not in Egr-1 null mice and that after partial hepatectomy such is significantly greater in the the null liver and In to this in hepatic regeneration in Egr-1 null mice results from a after the first wave of hepatocellular DNA of was in mice were to partial to and then 1 to and after partial In this analysis of hepatocellular only hepatocytes the of These of analysis were to the of the wave and the of the wave of hepatocellular DNA synthesis following partial hepatectomy Y. Kirillova I. Peschon J.J. Fausto N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1441-1446Crossref PubMed Scopus (828) Google Scholar). The data from this showed that hepatocellular is and Egr-1 null mice after partial hepatectomy significantly reduced in Egr-1 null mice after and Taken these data show that in Egr-1 null mice liver regeneration proceeds normally through the first round of hepatocellular DNA synthesis that hepatocellular cell cycle progression is significantly in and Egr-1 null mice after partial hepatectomy using the of hepatocytes that and after partial hepatectomy in and Egr-1 null mice for and liver from and Egr-1 null mice after partial hepatectomy and for hepatocellular during Liver Regeneration in Egr-1 of early molecular signaling events induced by partial hepatectomy and required for initiation of hepatocellular during liver regeneration have been the tumor necrosis cytokine signaling is for normal initiation of hepatic induction of and activation of hepatic after partial hepatectomy Y. Kirillova I. Peschon J.J. Fausto N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1441-1446Crossref PubMed Scopus (828) Google Scholar, C. Poli V. Taub R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). early signaling of and for normal liver regeneration is the induction of hepatic expression of L.E. Li D.E. Y. Ciliberto G. Poli V. Taub R. J. PubMed Scopus Google Scholar). This the that hepatic expression is These and other early signaling events the induction of expression of the and after partial hepatectomy and regulate hepatocellular progression and DNA synthesis (1Fausto N. J. Hepatol. 2000; 32: 19-31Abstract Full Text PDF PubMed Google Scholar). in to provide that the of hepatic regeneration in is of the first wave of hepatocellular DNA the regulation of these early signaling events was in Egr-1 null mice. the induction of and activation of were by and The results showed that of these is induced after partial hepatectomy in Egr-1 null and mice and in hepatic expression of and were by and the results showed in the expression of of these transcription factors after partial hepatectomy in Egr-1 null mice the regulation of expression of and E was and the results showed that the induction of of these cell cycle appropriately after partial hepatectomy in Egr-1 null mice. these data that the early signaling events to the round of hepatocellular progression normally in Egr-1 null mice. of p38 during Liver Regeneration in Egr-1 kinase is an important regulator of cell cycle including progression through subsequent to DNA synthesis C. Biol. Cell. 2001; PubMed Scopus Google Scholar, 12: PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar). In to hepatocellular cell cycle progression during liver regeneration in Egr-1 null mice is activation of the state of p38 kinase in and Egr-1 null regenerating liver were the of regulation of p38 in normal regenerating liver was by analysis of quiescent and regenerating liver for and The results showed that p38 is in quiescent from to after partial after partial and then after partial hepatectomy These were specific for regenerating liver as were not induced by not of p38 were in quiescent and regenerating liver all examined the in hepatic of p38 are by regulation of p38 and not by in the of p38 in regenerating liver from mice was that in Egr-1 null mice after partial This to progression through the round of hepatocellular and initiation of the round of DNA synthesis during liver regeneration. The results showed significantly greater of p38 in Egr-1 null liver liver and a of p38 in the activation of the p38 kinase kinase J. Cell. 2000; 12: PubMed Scopus Google Scholar), was in of these tissue and the results showed significantly greater of in Egr-1 null regenerating liver after partial hepatectomy and Together these results that the in cell cycle progression after the first round of hepatocellular DNA synthesis in Egr-1 null mice is p38 kinase cascade during Liver Regeneration in Egr-1 has been to regulate cell cycle progression through 12: PubMed Scopus Google Scholar) and through the mitotic to Science. PubMed Scopus Google Scholar). the in hepatocellular cell cycle progression in Egr-1 null mice after was examined and liver from and Egr-1 null mice were for mitotic after partial The results showed that mitotic after partial following the first wave of hepatocellular DNA is greater in Egr-1 null mice this not significance and progression through the mitotic spindle assembly checkpoint is in regenerating Egr-1 null hepatocytes was this these liver were to the of and mitotic in were as showed of as in the in The results showed of mitotic in regenerating liver from and Egr-1 null mice a significantly greater of mitotic in regenerating liver from mice in in Egr-1 null Taken these data show that mitotic progression in Egr-1 null regenerating liver is and the mitotic spindle assembly In to the of this mitotic in regenerating liver from and Egr-1 null mice after partial hepatectomy was The results showed mitotic from to in regenerating liver to mitotic this in Egr-1 null liver data not The that mitotic hepatocytes not in the regenerating Egr-1 null liver that the of the regenerative in these mice is progression through the mitotic is that hepatocytes are the mitotic checkpoint that are by such that not the was increase in hepatocellular by analysis not in Egr-1 null EGR-1 during Liver gene expression in the regenerating liver was characterized as part of the immediate-early gene expression program hepatocellular progression B.A. Diamond R.H. Taub R. J. PubMed Scopus Google Scholar, Y. S. Diamond R.H. Taub R. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). Egr-1 is during the regenerative response has not been The data reported that during liver regeneration Egr-1 is of cell cycle progression events subsequent to mitotic progression. the of Egr-1 gene expression during the hepatic regenerative response was Egr-1 were in quiescent and regenerating liver from mice after partial hepatectomy using The results showed an early increase in hepatic Egr-1 after partial hepatectomy and a subsequent increase in Egr-1 expression and after partial hepatectomy and not after hepatic Egr-1 expression from to after partial hepatectomy These data show that Egr-1 expression is increased in regenerating liver after the immediate-early gene expression EGR-1 protein expression was examined by analyses of from quiescent and regenerating The results showed the of an to EGR-1 in quiescent from to after partial then from to after followed by subsequent EGR-1 DNA has been in quiescent liver Y. S. Diamond R.H. Taub R. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar), the data reported here EGR-1 protein in quiescent the protein to EGR-1 was not in from Egr-1 null liver and after partial hepatectomy Taken these data show that EGR-1 is in regenerating liver during hepatocellular mitotic progression. during Liver Regeneration in Egr-1 has been as an important regulator of expression of the phosphatase of regenerating Y. S. Diamond R.H. Taub R. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, R.H. C. Greenbaum L.E. Haber B.A. Taub R. Am. J. Physiol. 1996; PubMed Google Scholar). was first during gene expression analyses quiescent to regenerating liver and was characterized as a gene a novel phosphatase induced during early liver regeneration R.H. D.E. Taub R. Mol. Cell. Biol. 1994; PubMed Scopus Google Scholar). The and studies have that EGR-1 is of the in cell Y. S. Diamond R.H. Taub R. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). These observations suggest that EGR-1 may an important in regulator of during liver regeneration. this, and may a regulator of mitotic the of induction of gene expression in regenerating liver was that in liver from Egr-1 null mice. expression was in quiescent and regenerating liver from mice after partial hepatectomy using The results showed that hepatic expression is increased in regenerating liver and after of and Egr-1 null liver after partial hepatectomy showed expression in the and of EGR-1 These data show that hepatic induction of expression following partial hepatectomy in is not during Liver Regeneration in Egr-1 to of EGR-1 that could involved in regulating hepatocellular mitotic progression during liver hepatic gene in and Egr-1 null liver after partial hepatectomy were other by microarray-based gene expression from regenerating liver after partial hepatectomy was used for this analysis EGR-1 protein is in regenerating liver and mitotic is in Egr-1 null regenerating liver this data were for expression was increased in regenerating liver from mice, such have a of in gene expression that by other of these and expression was in regenerating liver and and expression was greater in Egr-1 null regenerating liver were of the as in regenerating Cdc20, was of the that progression through the mitotic spindle assembly checkpoint G. M. Lin Y. H. G. Biol. 2000; PubMed Scopus Google Scholar, J. Biol. 2000; PubMed Scopus Google Scholar), and its expression in Egr-1 null mice could the in mitotic progression in Egr-1 null mice during liver regeneration. In to these data and to the of expression of during liver expression was by in and Egr-1 null regenerating expression in quiescent and regenerating liver was The results showed that hepatic gene expression is the first following partial and and after partial hepatectomy This of gene expression that of EGR-1 protein expression during liver regeneration. the expression of in regenerating and Egr-1 null liver after partial hepatectomy was the results of the this showed significantly greater expression in null liver Together these data suggest that gene expression is required for normal hepatocellular mitotic progression during liver in regenerating liver of expression analysis and Egr-1 null regenerating liver after partial expression is greater in regenerating liver are the in expression and 1 for protein protein protein 1 of of protein protein protein 1 in a in Egr-1 null regenerating liver of expression analysis and Egr-1 null regenerating liver after partial expression is greater in Egr-1 null regenerating liver are the in expression and protein AP-1, phosphatase protein 1 tumor protein of protein 1 protein kinase 1 gene factor protein cell protein functional protein protein protein kinase to 1 protein protein 1 protein protein protein protein in a The functional role of EGR-1 in regulating liver regeneration was first by studies that Egr-1 expression is increased during hepatocellular progression as part of the immediate-early gene response of the regenerating liver Y. S. Diamond R.H. Taub R. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). this of hepatic Egr-1 expression following partial hepatectomy is to that in a of other of cellular Y. S. Diamond R.H. Taub R. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Science. PubMed Scopus Google Scholar, D. Cell. Full Text PDF PubMed Scopus Google Scholar, B.A. D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). these EGR-1 to regulate progression during liver as has been for immediate-early gene induced in the regenerating liver G. P. 1997; PubMed Scopus Google Scholar). in the gene is a in the induction of cyclin expression and the progression through the round of hepatocellular DNA synthesis following partial hepatectomy G. P. 12: PubMed Scopus Google Scholar, G. P. PubMed Scopus Google Scholar). In the analyses of liver regeneration in Egr-1 null mice reported here show that the early signaling events to of quiescent hepatocytes the cell cycle and progression through the first wave of DNA synthesis hepatocellular cell cycle progression after that is in these These data for the first that EGR-1 is important for normal liver regeneration and a functional role for EGR-1 during liver of mitotic cell cycle progression. this, Egr-1 gene and EGR-1 protein expression are increased in regenerating liver that are subsequent to hepatocellular progression and that mitotic progression. the specific that regulate Egr-1 expression during liver regeneration have not been a of are of a of hepatocellular mitotic progression during liver regeneration to the reported here has been reported in a activation of Y. C. R. D.A. J. PubMed Scopus Google Scholar). The by inhibition of activation in mitotic in that was not the that an gene required for mitotic cell cycle progression. increased hepatocellular following partial a that was not in Egr-1 null mice not these observations the that Egr-1 expression during liver regeneration. In the of the EGR-1 gene a potential G. G. J. Cell. PubMed Scopus Google Scholar). of Egr-1 expression during liver regeneration are to and induction of Egr-1 gene expression has been to in mice in of these is L.E. Li D.E. Y. Ciliberto G. Poli V. Taub R. J. PubMed Scopus Google Scholar, Ciliberto G. Taub R. Hepatology. 2001; PubMed Scopus Google Scholar). reported here for Egr-1 null mice, liver regeneration is in and in of the is to the first round of hepatocellular DNA that and involved in signaling events for normal hepatocellular progression during liver regeneration. The microarray-based gene expression data here suggest that of the of EGR-1 regulation during liver regeneration is the APC, and it is to by and by the G. M. Lin Y. H. G. Biol. 2000; PubMed Scopus Google Scholar, J. Biol. 2000; PubMed Scopus Google Scholar). The observations reported here suggest that EGR-1 hepatocellular mitotic progression during liver regeneration by gene studies have that and in ES cells is normal J. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). Together the results reported this that the regulation of hepatocellular cell cycle progression in the regenerating liver and that of ES cells in cell from In regulation of cell cycle control in ES cells is to from that of cells the checkpoint in that progression from in cells, not in ES cells, is by the protein A. P. Biol. 12: Full Text Full Text PDF PubMed Scopus Google Scholar). Together these data suggest that regulation of mitotic progression hepatocytes and ES analyses of the molecular regulation of liver regeneration in response to partial hepatectomy not only to provide the signaling mechanisms that regulate the hepatic regenerative response and in regulation of cellular in and for the Egr-1 null mice and these and the by of for