Horizontal basal cell proliferation in the olfactory epithelium of transforming growth factor-alpha transgenic mice.
Transgenic mice in which overexpression of the transforming growth factor alpha (TGF-alpha) gene was directed by the keratin-14 promoter were used to study the regulation of cell cycle progression and proliferation in vivo in the olfactory epithelium. The level of TGF-alpha protein was 73% greater in the nasal-olfactory epithelium of the transgenic mice than in that of nontransgenic littermate controls. Increased levels of TGF-alpha protein were accompanied by a 5.8-fold selective increase in the proliferation of phenotypically characterized horizontal basal cells in the transgenics compared with nontransgenics; in contrast, globose basal cells exhibited a similar low level of proliferation in both transgenics and nontransgenics. The level of expression of epidermal growth factor receptor protein, the receptor for TGF-alpha, was also upregulated in the transgenics, indicating a role for the ErbB tyrosine kinase receptor family in the response to TGF-alpha in the olfactory epithelium. TGF-alpha overexpression was also associated with increased expression of several early cell-cycle-associated proteins, including the growth factor sensor cyclin D1, retinoblastoma, E2F-1 transcription factor, and cyclin E, indicating the progression of relatively quiescent progenitor cells in the G1 phase of the cell cycle toward the G1/S restriction point, after which the cells become refractive to mitogens. These results demonstrate a role for the growth factor TGF-alpha in the in vivo regulation of cell cycle progression and proliferation in the mitotically active olfactory epithelium in these transgenic mice.
Getchell
T V
TV
Department of Physiology, University of Kentucky, Lexington, USA.
Narla
R K
RK
Little
S
S
Hyde
J F
JF
Getchell
M L
ML
D000818:Animals; D002352:Carrier Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002455:Cell Division; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D019927:Cyclin E / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005786:Gene Expression Regulation; D016161:Genes, Retinoblastoma; D005813:Genes, Synthetic; D019382:Human Growth Hormone / Q000235:genetics; D006801:Humans; D053547:Keratin-14; D007633:Keratins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009831:Olfactory Mucosa / Q000166:cytology*; D018034:Olfactory Receptor Neurons / Q000166:cytology*; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000502:physiology*; D019076:Transgenes
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D019382:Human Growth Hormone; D019938:Cyclin D1; D007633:Keratins