Heparin-binding Epidermal Growth Factor-like Growth Factor Links Hepatocyte Priming with Cell Cycle Progression during Liver Regeneration

Mitchell, Claudia; Nivison, Mary; Jackson, Leslie F.; Fox, Richard; Lee, Dong Hoon; Campbell, Jean S.; Fausto, Nelson

doi:10.1074/jbc.m412372200

Cited by 145 publications

(124 citation statements)

References 24 publications

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…Mice lacking TGF␣ develop normally and liver regeneration is not impaired most likely because other EGFR ligands may compensate for its absence (22). Recently, heparin-binding EGF has been shown to regulate hepatocyte DNA replication after 70% PH (23). Similarly, mice lacking amphiregulin also displayed impaired hepatocyte proliferation and delayed induction of cyclin D1 after PH (19).…”

mentioning

confidence: 99%

The EGF receptor is required for efficient liver regeneration

Natarajan

Wagner²,

Sibilia³

2007

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

271

242

View full text Add to dashboard Cite

Mice lacking the EGF receptor (EGFR) die between midgestation and postnatal day 20 with various defects in neural and epithelial organs. Here, we generated mice carrying a floxed EGFR allele to inactivate the EGFR in fetal and adult liver. Perinatal deletion of EGFR in hepatocytes resulted in decreased body weight, whereas deletion in the adult liver did not affect body mass. Although liver function was not affected, after partial hepatectomy mice lacking EGFR in the liver showed increased mortality accompanied by increased levels of serum transaminases indicating liver damage. Liver regeneration was delayed in the mutants because of reduced hepatocyte proliferation. Analysis of cell cycle progression in EGFR-deficient livers indicated a defective G 1 –S phase entry with delayed transcriptional activation and reduced protein expression of cyclin D1 followed by reduced cdk2 and cdk1 expression. Impaired liver regeneration was accompanied by compensatory up-regulation of TNFα in the serum and prolonged activation of c-Jun. Moreover, p38α and NF-κB activation was reduced in regenerating mutant livers, indicating an impaired stress response after hepatectomy. Our studies demonstrate that EGFR is a critical regulator of hepatocyte proliferation in the initial phases of liver regeneration.

show abstract

mentioning

confidence: 99%

The EGF receptor is required for efficient liver regeneration

Natarajan

Wagner²,

Sibilia³

2007

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

271

242

View full text Add to dashboard Cite

show abstract

“…The initiation of liver regeneration has been termed the priming phase, in which normally quiescent hepatocytes gain proliferative competence and become responsive to hepatic growth factors. Hepatocyte growth factor, heparin bindingepidermal growth factor-like growth factor, and TGF-␣ then stimulate cell cycle progression, leading to DNA replication and cell proliferation (1)(2)(3). One hallmark of the priming phase is the induction of immediate early genes such as the proto-oncogenes c-myc and c-jun, and of proinflammatory cytokines (4,5).…”

mentioning

confidence: 99%

Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr4

Campbell¹,

Riehle

Brooling³

et al. 2006

The Journal of Immunology

Self Cite

101

121

View full text Add to dashboard Cite

TNF and IL-6 are considered to be important to the initiation or priming phase of liver regeneration. However, the signaling pathways that lead to the production of these cytokines after partial hepatectomy (PH) have not been identified. Enteric-derived LPS appears to be important to liver regeneration, possibly by stimulating proinflammatory cytokine production after surgery. To determine whether LPS signaling pathways are involved in the regulation of the proinflammatory cytokines TNF and IL-6 during the priming phase of liver regeneration, we performed PH on mice lacking the TLRs Tlr4 and Tlr2, the LPS coreceptor, Cd14, and Myd88, an adapter protein involved in most TLR and IL-1R pathways. In MyD88 knockout (KO) mice after PH, both liver Tnf mRNA and circulating IL-6 levels were severely depressed compared with heterozygous or wild-type mice. Activation of STAT-3 and three STAT-3 responsive genes, Socs3, Cd14, and serum amyloid A2 were also blocked. In contrast, Tlr4, Tlr2, and Cd14 KO mice showed no deficits in the production of IL-6. Surprisingly, none of these KO mice showed any delay in hepatocyte replication. These data indicate that the LPS receptor TLR4, as well as TLR2 and CD14, do not play roles in regulating cytokine production or DNA replication after PH. In contrast, MyD88-dependent pathways appear to be responsible for TNF, IL-6, and their downstream signaling pathways.

show abstract

“…4 Indeed, hepatocyte growth factor and cytokines (interleukin-6 [1L-6]) promoted hepatic survival by stimulating liver regeneration and provided hepatoprotection in a variety of liver injury models, including Fas. [5][6][7][8] Insulin-like growth factor binding protein-1, 9,10 amphiregulin, 11,12 and heparin-binding epidermal growth factor 13 also displayed potent hepatoprotective or mitogenic effects. Thus, the identification of critical factors for in vivo antiapoptotic and mitogenic signaling pathways is of clinical interest.…”

mentioning

confidence: 99%

Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice

et al. 2006

View full text Add to dashboard Cite

Reg2/RegIII␤ is the murine homologue of the human secreted HIP/PAP C-type lectin. HIP/PAP transgenic mice were protected against acetaminophen-induced acute liver failure and were stimulated to regenerate post-hepatectomy. To assess the role of Reg2, we used Reg2؊/؊ mice in a model of fulminant hepatitis induced by Fas and in the post-hepatectomy regeneration. Within 4 hours of J0-2 treatment (0.5 g/g), only 50% of the Reg2؊/؊ mice were alive but with an increased sensitivity to Fas-induced oxidative stress and a decreased level of Bcl-xL. In contrast, HIP/PAP transgenic mice were resistant to Fas, with HIP/PAP serving as a sulfhydryl buffer to slow down decreases in glutathione and Bcl-xL. In Reg2؊/؊ mice, liver regeneration was markedly impaired, with 29% mortality and delay of the S-phase and the activation of ERK1/2 and AKT. Activation of STAT3 began on time at 3 hours but persisted strongly up to 72 hours despite significant accumulation of SOCS3. Thus, Reg2 deficiency induced exaggerated IL-6/STAT-3 activation and mito-inhibition. Because the Reg2 gene was activated between 6 and 24 hours after hepatectomy in wild-type mice, Reg2 could mediate the TNF-␣/IL-6 priming signaling by exerting a negative feedback on STAT3/IL-6 activation to allow the hepatocytes to progress through the cell cycle. In conclusion, Reg2 deficiency enhanced liver sensitivity to Fas-induced oxidative stress and delayed liver regeneration with persistent TNF-␣/IL6/STAT3 signaling. In contrast, overexpression of human HIP/PAP promoted liver resistance to Fas and accelerated liver regeneration with early activation/deactivation of STAT3. Reg2/HIP/PAP is therefore a critical mitogenic and antiapoptotic factor for the liver. (HEPATOLOGY 2006;44:1452-1464 F as/FasL (APO-1, CD95) interaction is involved in many pathological situations such as graft-versushost disease, liver transplant and major surgical resection, hepatitis B and C, acute alcoholic hepatitis, drug overdose, and some biliary diseases. Fas activation-induced acute liver failure is characterized by massive hepatic necrosis/apoptosis. Survival of patients depends on the speed with which quiescent liver cells re-enter the cell

show abstract

Heparin-binding Epidermal Growth Factor-like Growth Factor Links Hepatocyte Priming with Cell Cycle Progression during Liver Regeneration

Cited by 145 publications

References 24 publications

The EGF receptor is required for efficient liver regeneration

The EGF receptor is required for efficient liver regeneration

Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr4

Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice

Contact Info

Product

Resources

About