Diverse expression of ErbB receptor proteins during rat liver development and regeneration

Carver, Robert; Stevenson, Mary C.; Scheving, Lawrence A.; Russell, William E.

doi:10.1053/gast.2002.37060

Cited by 93 publications

(80 citation statements)

References 39 publications

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“…1 As previously mentioned, AR is a ligand of the EGF-R, a receptor that is highly expressed in adult hepatocytes. 20,21 In agreement with this, treatment of isolated rat hepatocytes with AR induced rapid and transient tyrosine phosphorylation of the EGF-R ( Figure 3B). The MEK/ERK and PI-3K pathways are viewed as the main signaling cascades in the mitogenic response of hepatocytes to growth factors.…”

Section: Amphiregulin Induces Dna Synthesis In Isolated Hepatocytessupporting

confidence: 83%

Amphiregulin: An early trigger of liver regeneration in mice

et al. 2005

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See editorial on page 504. Background & Aims:Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy. Methods: Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of amphiregulin were studied in isolated hepatocytes. The in vivo role of amphiregulin in liver regeneration after partial hepatectomy was analyzed in amphiregulin-null mice. Results: Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1␤ and prostaglandin E 2 , but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor ␣. We show that amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, amphiregulin-null mice display impaired proliferative responses after partial liver resection. Conclusions: Our findings indicate that amphiregulin is an earlyresponse growth factor that may contribute to the initial phases of liver regeneration.

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Section: Amphiregulin Induces Dna Synthesis In Isolated Hepatocytessupporting

confidence: 83%

Amphiregulin: An early trigger of liver regeneration in mice

et al. 2005

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“…conditional EGF receptor knockout mice ͉ cyclin D1 ͉ hepatocyte proliferation ͉ liver function ͉ partial hepatectomy T he EGF receptor (EGFR) is highly expressed in the adult liver and has been proposed to play an important role during liver development, function, and regeneration (1). Together with erbB2/ neu, erbB3, and erbB4, the EGFR/erbB1 belongs to the ErbB family of receptor tyrosine kinases which can homo-or heterodimerize on ligand stimulation.…”

mentioning

confidence: 99%

The EGF receptor is required for efficient liver regeneration

Natarajan

Wagner²,

Sibilia³

2007

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

267

239

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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.

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“…17 The effect of EGF on proliferation and motility of progenitor(-like) cells, other than pancreatic, has been extensively described. [18][19][20][21] Moreover, EGF receptors have been detected in adult human and in developing mouse pancreatic ducts [22][23][24] and are critical for proper pancreas development. 25 The present study analyzes the expression and function of the ErbB family in cultured adult human pancreatic duct cells.…”

Section: Discussionmentioning

confidence: 99%

EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade

Rescan

Bras

Lefebvre

et al. 2005

Laboratory Investigation

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Human postnatal pancreatic duct cells are a potential source of new beta cells. Factors regulating proliferation of human pancreatic duct cells in vitro are unknown. In several other cell types, this process is influenced by ligands of the ErbB receptor family. The expression and functionality of the ErbB family members and their possible role in duct cell proliferation were determined. In cultured adult human pancreatic duct cells the different members of the ErbB family (ErbB1-4) were present at transcript and protein level. Stimulation of the duct cells with epidermal growth factor (EGF) and betacellulin results in Tyr-phosphorylation of ErbB1 and ErbB2, followed by activation of Shc, MEK1/2 and ERK1/2. Duct cells with activated ErbB signaling changed morphology and motility. EGF induced proliferation of a fraction of the duct cells and treatment with PD98059 prevented Ki67 expression in EGF-supplemented cells. When transduced with recombinant adenovirus expressing constitutively activated MEK1, duct cells proliferate and spread even in the absence of EGF. Importantly, the adult human duct cells retain their capacity to recapitulate ngn3-induced embryonic (neuro)endocrine differentiation after proliferation. Therefore, the present data support a possible role for human adult pancreatic duct cells, following expansion and transdifferentiation, as a source of insulin by transplantation to type I diabetes patients.

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Diverse expression of ErbB receptor proteins during rat liver development and regeneration

Cited by 93 publications

References 39 publications

Amphiregulin: An early trigger of liver regeneration in mice

Amphiregulin: An early trigger of liver regeneration in mice

The EGF receptor is required for efficient liver regeneration

EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade

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