Delayed hepatocellular mitotic progression and impaired liver regeneration in early growth response-1-deficient mice.
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/ebpalpha, C/ebpbeta, 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.
Liao
Yunjun
Y
Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, MO, USA.
Shikapwashya
Olga N
ON
Shteyer
Eyal
E
Dieckgraefe
Brian K
BK
Hruz
Paul W
PW
Rudnick
David A
DA
D000705:Anaphase; D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D064199:Cdc20 Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D004396:Coloring Agents / Q000494:pharmacology; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051766:Early Growth Response Protein 1; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D015151:Immunoblotting; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008677:Metaphase; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000378:metabolism; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D018797:Cell Cycle Proteins; D004396:Coloring Agents; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D012313:RNA; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine