scholarly journals Interactive Effects of c-myc and Transforming Growth Factor α Transgenes on Liver Tumor Development in Simian Virus 40 T Antigen Transgenic Mice

1998 ◽  
Vol 35 (4) ◽  
pp. 283-291 ◽  
Author(s):  
A. Enomoto ◽  
E. P. Sandgren ◽  
R. R. Maronpot
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Liver Tumors ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Transforming Growth Factor Α ◽  
Neoplastic Lesions ◽  
Factor Α

To analyze the effects of c- myc and transforming growth factor α (TGFα) on hepatocarcinogenesis induced by simian virus 40 T antigen (TAg), livers from single and bitransgenic mice, 3 to 11 mice per line, were examined morphologically 1 to 8 weeks after birth. Mice carrying c- myc or TGFα alone exhibited centrilobular hypertrophy and increased apoptosis (c- myc mice only) of hepatocytes after 3 or 4 weeks of age, but no detectable changes in cell proliferation or proliferative lesions were observed in either line during the 8 weeks. Mice carrying TAg alone exhibited increased cell proliferation, apoptosis, and dysplasia of hepatocytes with notably high mitotic and apoptotic indices as major changes before development of putative preneoplastic lesions after 4 weeks of age and neoplastic lesions after 6 weeks. In bitransgenic mice coexpressing c- myc or TGFα with TAg, nonproliferative lesions and mitotic and apoptotic indices were similar to those in mice carrying TAg alone. In TAg X c- myc bitransgenic mice, however, both preneoplastic and neoplastic lesions developed sooner and grew more rapidly than those in TAg mice, whereas in TAg X TGFα bitransgenic mice, rapid tumor growth was the principle observation. Because of the effects of transgene coexpression, livers from TAg X c- myc and TAg X TGFα mice had multiple tumors as early as 3 and 6 weeks of age, respectively. The results indicate cooperative functions of c- myc and TGFα with TAg during development and/or growth of liver tumors in vivo.

Horizontal basal cell proliferation in the olfactory epithelium of transforming growth factor-α transgenic mice

2000 ◽  
Vol 299 (2) ◽  
pp. 185-192
Author(s):  
Thomas V. Getchell ◽  
Rama Krishna Narla ◽  
Susan Little ◽  
James F. Hyde ◽  
Marilyn L. Getchell
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Olfactory Epithelium ◽  
Basal Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Α ◽  
Factor Α

Transforming Growth Factor-α with Insulin Induces Proliferation in Rat Utricular Extrasensory Epithelia

1998 ◽  
Vol 118 (6) ◽  
pp. 816-824 ◽  
Author(s):  
ALICE L. KUNTZ ◽  
ELIZABETH C. OESTERLE
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Hair Cell ◽  
Inner Ear ◽  
Transforming Growth Factor ◽  
Tritiated Thymidine ◽  
Cell Loss ◽  
Hair Cell Loss ◽  
Transforming Growth Factor Α ◽  
Factor Α

Hair cell loss in the human inner ear leads to sensorineural hearing loss and vestibular dysfunction. Recent studies suggest that exogenous addition of growth factors, for example, transforming growth factor-α with insulin, may stimulate the production of new supporting cells and hair cells in the mature mammalian vestibular sensory epithelium. Before any growth factor can be seriously considered for the treatment of clinical problems related to hair cell loss, its effects on the extrasensory epithelia must also be fully explored. The aim of this study was to determine whether transforming growth factor-α and insulin stimulate cell proliferation in rodent vestibular extrasensory epithelia. The cell proliferation marker, tritiated thymidine, was infused along with transforming growth factor-α, insulin, or transforming growth factor-α plus insulin into the inner ears of adult rats via osmotic pumps. Effects of the test agents were assessed on normal and drug-damaged utricles. Drug damage was produced by delivering gentamicin directly into the inner ear before the infusion of test agent. Animals were killed 4 or 10 days after pump placement. Utricles were sectioned, processed for autoradiography, and examined for labeled cells within the extrasensory epithelia. In normal animals, transforming growth factor-α plus insulin stimulated DNA synthesis in all regions of the extrasensory epithelia, suggesting that these agents are mitogenic for these tissues. (Otolaryngol Head Neck Surg 1998;118:816-24.)

scholarly journals Metalloproteinases and Transforming Growth Factor-α Mediate Substance P-induced Mitogen-activated Protein Kinase Activation and Proliferation in Human Colonocytes

2004 ◽  
Vol 279 (44) ◽  
pp. 45519-45527 ◽  
Author(s):  
Hon-Wai Koon ◽  
Dezheng Zhao ◽  
Xi Na ◽  
Mary P. Moyer ◽  
Charalabos Pothoulakis
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Chronic Colitis ◽  
Transforming Growth Factor Α ◽  
Egfr Ligands ◽  
Mitogen Activated Protein ◽  
Factor Α

Substance P (SP) participates in acute intestinal inflammation via binding to the G-protein-coupled neurokinin-1 receptor (NK-1R) and release of proinflammatory cytokines from colonic epithelial cells. SP also stimulates cell proliferation, a critical event in tissue healing during chronic colitis, via transactivation of the epidermal growth factor (EGF) receptor (EGFR) and activation of mitogen-activated protein kinase (MAPK). Here we examined the mechanism by which SP induces EGFR and MAPK activation. We used non-transformed human NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) as well as untransfected U373 MG cells expressing high levels of endogenous NK-1R. Exposure of both cell lines to SP (10–7m) stimulated EGFR activation (1 min) followed by extracellular signal-regulated protein kinase (ERK1/2) activation (2–5 min). SP-induced ERK1/2 activation was blocked by pretreatment with the metalloproteinase inhibitor Batimastat/GM6001, the EGFR phosphorylation inhibitor AG1478, and the tumor necrosis factor-α-converting enzyme (TACE) inhibitor TAPI-1. Pretreatment with antibodies against potential EGFR ligands suggested that transforming growth factor-α (TGFα), but not the other EGFR ligands EGF, heparin-binding EGF, or amphiregulin, mediates SP-induced EGFR transactivation. SP stimulated TGFα release into the extracellular space that was measurable within 2 min, and this release was inhibited by metalloproteinase inhibitors and the TACE inhibitor TAPI-1. SP also induced MAPK-mediated cell proliferation that was inhibited by TACE, matrix metalloproteinase (MMP), EGFR, and MEK1 inhibitors. Thus, in human colonocytes, NK-1R-induced EGFR and MAPK activation and cell proliferation involve matrix metalloproteinases (most likely TACE) and the release of TGFα. These signaling mechanisms may be involved in the protective effects of NK-1R in chronic colitis.

Horizontal basal cell proliferation in the olfactory epithelium of transforming growth factor-α transgenic mice

1999 ◽  
Vol 299 (2) ◽  
pp. 185-192
Author(s):  
Thomas V. Getchell ◽  
Rama Krishna Narla ◽  
Susan Little ◽  
James F. Hyde ◽  
Marilyn L. Getchell
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Olfactory Epithelium ◽  
Basal Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Α ◽  
Factor Α

scholarly journals The Tetraspanin Cd9 Associates with Transmembrane TGF-α and Regulates TGF-α–Induced Egf Receptor Activation and Cell Proliferation

2000 ◽  
Vol 148 (3) ◽  
pp. 591-602 ◽  
Author(s):  
Wen Shi ◽  
Huizhou Fan ◽  
Lillian Shum ◽  
Rik Derynck
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Receptor Activation ◽  
Tyrosine Kinase Receptor ◽  
Transforming Growth Factor Α ◽  
Egfr Activation ◽  
Membrane Spanning ◽  
Factor Α

Transforming growth factor-α (TGF-α) is a member of the EGF growth factor family. Both transmembrane TGF-α and the proteolytically released soluble TGF-α can bind to the EGF/TGF-α tyrosine kinase receptor (EGFR) and activate the EGFR-induced signaling pathways. We now demonstrate that transmembrane TGF-α physically interacts with CD9, a protein with four membrane spanning domains that is frequently coexpressed with TGF-α in carcinomas. This interaction was mediated through the extracellular domain of transmembrane TGF-α. CD9 expression strongly decreased the growth factor– and PMA- induced proteolytic conversions of transmembrane to soluble TGF-α and strongly enhanced the TGF- α–induced EGFR activation, presumably in conjunction with increased expression of transmembrane TGF-α. In juxtacrine assays, the CD9-induced EGFR hyperactivation by transmembrane TGF-α resulted in increased proliferation. In contrast, CD9 coexpression with transmembrane TGF-α decreased the autocrine growth stimulatory effect of TGF-α in epithelial cells. This decrease was associated with increased expression of the cdk inhibitor, p21CIP1. These data reveal that the association of CD9 with transmembrane TGF-α regulates ligand-induced activation of the EGFR, and results in altered cell proliferation.

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