Transforming growth factor beta regulation of epidermal growth factor receptor in ectocervical epithelial cells.
Transforming growth factor beta (TGF beta) is a pluripotent modulator of cell function and an important suppressor of cervical epithelial cell proliferation. In the present study, we examine the effects of TGF beta 1 on the level and activity of the epidermal growth factor receptor (EGFR) in HPV-16 immortalized cervical epithelial cells. In ECE16-1 cells, increased EGFR levels are observed within 24 h after initiation of TGF beta 1 treatment and levels continue to increase with time. This increase is correlated with a TGF beta 1-dependent decrease in proliferation rate. Scatchard analysis indicates that the population of EGFR sites induced by TGF beta 1 have a low affinity for EGF (Kd = 4.08 nM) compared to the receptors present prior to TGF beta 1 treatment (Kd = 0.3 and 1.6 nM). TGF beta 1 treatment also reduces EGFR kinase autophosphorylation activity. Cell cycle studies indicate that TGF beta 1-treated cells arrest in the G1 phase of the cell cycle and that regulation of EGFR level was independent of cell cycle stage in both TGF beta 1-treated and untreated cells. However, EGFR level was related to the G1 phase time. Parallel studies indicate that a TGF beta 1-dependent increase in p53 level is also correlated with increased time spent in G1. These results suggest that TGF beta 1 inhibition of ECE16-1 cell proliferation may act both by the replacement of high affinity/high kinase activity EGFR sites with low affinity/low kinase activity EGFR sites and a p53-mediated cell cycle arrest.
Jacobberger
J W
JW
Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Sizemore
N
N
Gorodeski
G
G
Rorke
E A
EA
D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D002584:Cervix Uteri / Q000166:cytology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism*; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D010766:Phosphorylation; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D066246:ErbB Receptors