X. Trefoil peptide and EGF receptor/ligand transgenic mice

2000 ◽  
Vol 278 (4) ◽  
pp. G501-G506 ◽  
Author(s):  
Andrew S. Giraud

The use of genetically engineered mice with both gain-of-function and loss-of-function mutations has been particularly informative about the normal and pathophysiological actions of a number of regulatory peptides of the gastrointestinal tract. This review highlights some of the major findings pertinent to the epidermal growth factor (EGF) receptor and its ligands, particularly the major gut ligand transforming growth factor-α, as well as the trefoil peptides. Both of these peptide families have important local actions in maintaining tissue homeostasis and repair after injury, and when mechanisms governing their regulation are disrupted they may contribute to disease progression. Future applications of transgenic technology to these areas are likely to be productive in furthering our understanding of the biology of these peptides in health and disease.

1999 ◽  
Vol 276 (5) ◽  
pp. G1105-G1116 ◽  
Author(s):  
Kimitoshi Kato ◽  
Monica C. Chen ◽  
Minh Nguyen ◽  
Frank S. Lehmann ◽  
Daniel K. Podolsky ◽  
...  

Restitution, the lateral migration of cells over an intact basement membrane, maintains mucosal integrity. We studied the regulation of migration and proliferation of enzyme-dispersed canine oxyntic mucosa cells in primary culture. Confluent monolayers were wounded and cultured in serum-free medium, and cells migrating into the wound were counted. [3H]thymidine incorporation into DNA was studied using subconfluent cultures. Considerable migration occurred in untreated monolayers; however, epidermal growth factor (EGF), transforming growth factor (TGF)-α, basic fibroblast growth factor (bFGF), insulin-like growth factor I (IGF-I), two trefoil peptides, and interleukin (IL)-1β further enhanced migration. The specific EGF receptor (EGFR) monoclonal antibody, MAb-528, inhibited both basal and TGF-α- or IL-1β-stimulated migration, but not the response to trefoil peptide, bFGF, or IGF-I. Exogenous TGF-β inhibited cell proliferation but did not alter migration. Immunoneutralization with anti-TGF-β blocked the response to exogenous TGF-β and produced a small enhancement of basal thymidine incorporation but did not attenuate basal or TGF-α-stimulated migration. In conclusion, endogenous EGFR ligands regulate proliferation and migration. TGF-β inhibits mitogenesis; it did not upregulate migration in these cultures. Although bFGF, IGF-I, and IL-1β enhance gastric epithelial migration, only IL-1β acted in a TGF-α-dependent fashion.


1997 ◽  
Vol 272 (6) ◽  
pp. G1540-G1549 ◽  
Author(s):  
G. A. Cook ◽  
N. D. Yeomans ◽  
A. S. Giraud

Trefoil peptides are gut peptides that have been implicated in the repair of the gastric mucosa after injury. Previous studies suggest that epidermal growth factor (EGF) receptor ligands may induce the expression of trefoil peptides. Because transforming growth factor-alpha (TGF-alpha) is a major EGF receptor ligand in the gut, we tested the hypothesis that mice with a TGF-alpha null mutation (knockout) would have reduced trefoil peptide expression compared with wild-type controls after gastric ulceration. The rate of macroscopic ulcer healing was the same in knockout and wild-type mice. Spasmolytic polypeptide (SP) and intestinal trefoil factor (ITF) expression were quantified in tissue and gastric lavage. SP and ITF levels in tissue fell within 48 h of ulceration (P < 0.05), but secretion into gastric juice was unchanged. ITF peptide expression was increased (as was SP expression) in wild-type but not knockout mice 42 and 72 days after injury (P < 0.05). The induction of SP and ITF expression in the latter stages of injury repair has a TGF-alpha-dependent component and suggests a role for these peptides in gastric differentiation and cell positioning.


1991 ◽  
Vol 75 (1) ◽  
pp. 97-102 ◽  
Author(s):  
Motohiko Maruno ◽  
John S. Kovach ◽  
Patrick J. Kelly ◽  
Takehiko Yanagihara

✓ Surgical specimens from six benign and 16 malignant human gliomas were investigated immunohistochemically to correlate the degree of malignancy, the distribution of transforming growth factor-alpha (TGF-α) and epidermal growth factor (EGF) receptor, and the potential for cell proliferation using monoclonal antibodies to TGF-α, EGF receptor, and Ki-67. Fourteen (88%) of the malignant gliomas and one (17%) of the benign gliomas were found to be positive for TGF-α, and 14 (88%) of the malignant gliomas and two (33%) of the benign gliomas expressed EGF receptor. The proliferation index with Ki-67 was 18.8% ± 8.1% (mean ± standard deviation) in malignant gliomas and 1.9% ± 1.8% in benign gliomas. In general, cells positive for EGF receptor and Ki-67 were randomly distributed throughout the tumor tissue, and cells positive for TGF-α tended to be clustered without obvious relationship to areas of necrosis or blood vessels. In some tumors, cells positive for TGF-α, EGF receptor, and Ki-67 were associated in a focal distribution. The more frequent expression of TGF-α and EGF receptor in the highly proliferative malignant gliomas is compatible with a role for TGF-α and EGF receptor in the induction or stimulation of malignant gliomas.


Peptides ◽  
1992 ◽  
pp. 410-412
Author(s):  
Donna E. Davies ◽  
Audrey Richter ◽  
J. Wayne Conlan ◽  
Clement Higginbotham ◽  
Michael E. Ward ◽  
...  

1992 ◽  
Vol 281 (3) ◽  
pp. 729-733 ◽  
Author(s):  
G G Skouteris ◽  
M McMenamin

Primary hepatocytes stimulated with epidermal growth factor (EGF) secrete prostaglandins into the culture medium as soon as 1 h after the addition of the EGF. Transforming growth factor-alpha (TGF alpha), a potent hepatocyte mitogen, shares the same receptor with EGF, and its expression is increased after partial hepatectomy. TGF alpha is also secreted in culture. We have observed that TGF alpha induced hepatocyte DNA synthesis (30 h after addition) and at the same time stimulated the production of prostaglandins E2 and F2 alpha by the cultured hepatocytes. Indomethacin at 20-100 microM inhibited the TGF alpha-induced hepatocyte DNA synthesis, and this effect was specifically due to the inhibition of prostaglandin formation. Indomethacin also inhibited a TGF-alpha-induced increase in hepatocyte c-myc expression, indicating that prostaglandins mediate this increase, as previously shown for EGF. TGF alpha increased the expression of the EGF receptor gene, and this was prevented by the presence of an antibody against TGF alpha in the culture medium. We therefore suggest that TGF alpha induces hepatocyte proliferation either through coupling with its receptor (i.e. the EGF receptor) or by subsequent phosphorylation of lipocortin I. This leads to activation of phospholipase. A2, which seems to regulate the metabolism of arachidonic acid and the formation of prostaglandins. Thus hepatocyte proliferation in vitro appears to be controlled by a self-regulatory autocrine pathway involving activation of phospholipase A2 and secretion of prostaglandins and TGF alpha.


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