Increased expression of the N-myc gene during normal and neoplastic rat liver growth

Corral, Marisol; Paris, Brigitte; Guguen‐Guillouzo, Christiane; Corcos, Daniel; Kruh, Jacques; Defer, Nicole

doi:10.1016/0014-4827(88)90146-2

Cited by 32 publications

(15 citation statements)

References 28 publications

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“…It is also interesting to note that at 24 h post-PH, we observe a sixfold stimulation of N-myc and c-myc gene expression compared with wild-type livers at similar times after PH (data not shown). This result suggests that nuclear translocation of the HFH-11B protein may be maintaining expression of the myc family members, which exhibit biphasic expression during liver regeneration (4,35). Furthermore, our transgenic liver regeneration studies are consistent with the polyploid phenotype of hfh11/trident-deficient embryonic hepatocytes, suggesting that HFH-11/Trident plays a role in coordinating the timing of DNA replication and mitosis (29).…”

Section: Discussionsupporting

confidence: 75%

Premature Expression of the Winged Helix Transcription Factor HFH-11B in Regenerating Mouse Liver Accelerates Hepatocyte Entry into S Phase

Ye¹,

Holterman

Yoo³

et al. 1999

Molecular and Cellular Biology

167

263

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Two-thirds partial hepatectomy (PH) induces differentiated cells in the liver remnant to proliferate and regenerate to its original size. The proliferation-specific HNF-3/fork head homolog-11B protein (HFH-11B; also known as Trident and Win) is a family member of the winged helix/fork head transcription factors and in regenerating liver its expression is reactivated prior to hepatocyte entry into DNA replication (S phase). To examine whether HFH-11B regulates hepatocyte proliferation during liver regeneration, we used the ؊3-kb transthyretin (TTR) promoter to create transgenic mice that displayed ectopic hepatocyte expression of HFH-11B. Liver regeneration studies with the TTR-HFH-11B mice demonstrate that its premature expression resulted in an 8-h acceleration in the onset of hepatocyte DNA replication and mitosis. This liver regeneration phenotype is associated with protracted expression of cyclin D1 and C/EBP␤, which are involved in stimulating DNA replication and premature expression of M phase promoting cyclin B1 and cdc2. Consistent with the early hepatocyte entry into S phase, regenerating transgenic livers exhibited earlier expression of DNA repair genes (XRCC1, mHR21spA, and mHR23B). Furthermore, in nonregenerating transgenic livers, ectopic HFH-11B expression did not elicit abnormal hepatocyte proliferation, a finding consistent with the retention of the HFH-11B transgene protein in the cytoplasm. We found that nuclear translocation of the HFH-11B transgene protein requires mitogenic signalling induced by PH and that its premature availability in regenerating transgenic liver allowed nuclear translocation to occur 8 h earlier than in wild type.The mammalian liver is one of the few adult organs capable of completely regenerating itself in response to cellular injury from toxins, viral infections, or tissue removal (15,38,46). Liver regeneration after two-thirds partial hepatectomy (PH) represents a balance between hepatocyte proliferation and the maintenance of hepatocyte-specific gene expression required for liver homeostasis (22,46). A potent activation of hepatocyte immediate early transcription factors is observed during liver regeneration and includes c-Jun, c-Fos, c-Myc, NF-B, signal transducers, and activators of transcription 3 (stat3) and the CCAAT/enhancer protein ␤ (C/EBP␤) genes (7,9,25,46). Furthermore, maintenance of hepatocyte-specific gene transcription is coincident with sustained expression of hepatocyte nuclear factor genes (16,20,41). More recent genetic data demonstrated that the cytokine interleukin-6 (IL-6) plays an important role in establishing responsiveness of hepatocytes to growth factors which are released after liver injury (8,54). In a PH model of liver regeneration, homozygous null interleukin-6 (IL-6) or type 1 tumor necrosis factor receptor (TNFR-I) mice exhibited a 70% reduction in hepatocyte replication and this proliferation defect was eliminated by an intraperitoneal injection of IL-6 prior to surgery (8,43,54). This proliferation defect was accompanied by a failur...

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Section: Discussionsupporting

confidence: 75%

Premature Expression of the Winged Helix Transcription Factor HFH-11B in Regenerating Mouse Liver Accelerates Hepatocyte Entry into S Phase

Ye¹,

Holterman

Yoo³

et al. 1999

Molecular and Cellular Biology

167

263

View full text Add to dashboard Cite

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“…To restore liver mass after PH, quiescent hepatocytes must undergo a G 0 -to-G 1 transition and enter S phase (34); the c-myc and n-myc genes are rapidly induced after PH (10,35,36). We therefore analyzed whether liver regeneration was affected in pIpC-injected c-myc fl/fl ;mx-cre ϩ mice.…”

Section: Resultsmentioning

confidence: 99%

“…C-Myc expression promotes the transition from G 0 ͞G 1 to S phase of the cell cycle in multiple cell types, including hepatocytes, by regulating cyclin͞cyclin-dependent kinase complexes (6)(7)(8). The G 0 ͞G 1 to S-phase transition observed in hepatocytes of regenerating livers after partial hepatectomy (PH) correlates with rapid induction of c-myc and n-myc transcripts (9,10). In limiting serum conditions, c-myc overexpression induces apoptosis in fibroblast and myeloid cell lines (11,12).…”

mentioning

confidence: 99%

c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver

Baena

Gandarillas

Vallespinós

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The c-Myc protein is a transcription factor implicated in the regulation of multiple biological processes, including cell proliferation, cell growth, and apoptosis. In vivo overexpression of c-myc is linked to tumor development in a number of mouse models. Here, we show that perinatal inactivation of c-Myc in liver causes disorganized organ architecture, decreased hepatocyte size, and cell ploidy. Furthermore, c-Myc appears to have distinct roles in proliferation in liver. Thus, postnatal hepatocyte proliferation does not require c-Myc, whereas it is necessary for liver regeneration in adult mice. These results show novel physiological functions of c-myc in liver development and hepatocyte proliferation and growth.

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“…During liver regeneration in rats there is a sequential and regulated expression of several proto-oncogenes (12,13,20,22,26,32,36,58). In the first 2 to 4 h after partial hepatectomy there are transient changes in the steady-state levels of c-fos, c-jun (J. E. Mead, M. FitzGerald, and N. Fausto, unpublished data), and c-myc mRNAs as quiescent hepatocytes enter the cell cycle.…”

mentioning

confidence: 99%

c-myc, c-fos, and c-jun regulation in the regenerating livers of normal and H-2K/c-myc transgenic mice.

Morello¹,

FitzGerald²,

Babinet³

et al. 1990

Mol. Cell. Biol.

103

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We investigated the mechanisms of regulation of c-myc, c-fos, and c-jun at the early stages of liver regeneration in mice. We show that the transient increase in steady-state levels of c-myc mRNA at the start of liver regeneration is most probably regulated by posttranscriptional mechanisms. Although there was a marked increase in c-myc transcriptional initiation shortly after partial hepatectomy, a block in elongation prevented the completion of most transcripts. To gain further information on the mechanism of regulation of c-myc expression during liver regeneration, we used transgenic mice harboring the human c-myc gene driven by the H-2K promoter. In these animals, the murine c-myc responded to the growth stimulus generated by partial hepatectomy, whereas the expression of the transgene was constitutive and did not change in the regenerating liver. However, the mRNA from both genes increased markedly after cycloheximide injection, suggesting that the regulation of c-myc mRNA abundance in the regenerating liver differs from that occurring after protein synthesis inhibition. Furthermore, we show that in normnal mice c-fos and c-jun mRNA levels and transcriptional rates increase within 30 min after partial hepatectomy. c-fos transcriptional elongation was restricted in nongrowing liver, but the block was partially relieved in the regenerating liver. Nevertheless, for both c-fos and c-jun, changes in steady-state mRNA detected after partial hepatectomy were much greater than the transcriptional increase. In the regenerating liver of H-2KIc-myc mice, c-fos and c-jun expression was diminished, whereas mouse c-myc expression was enhanced in comparison with that in nontransgenic animals.

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Increased expression of the N-myc gene during normal and neoplastic rat liver growth

Cited by 32 publications

References 28 publications

Premature Expression of the Winged Helix Transcription Factor HFH-11B in Regenerating Mouse Liver Accelerates Hepatocyte Entry into S Phase

Premature Expression of the Winged Helix Transcription Factor HFH-11B in Regenerating Mouse Liver Accelerates Hepatocyte Entry into S Phase

c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver

c-myc, c-fos, and c-jun regulation in the regenerating livers of normal and H-2K/c-myc transgenic mice.

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