Regulation of epidermal growth factor receptor gene expression in murine embryonal carcinoma cells

The protooncogene c-erbB1 [epidermal growth factor receptor (EGF-R)] is expressed in a wide variety of cell types and in most adult tissues. The precise roles of the EGF-R in vivo are largely unknown, especially their role in growth and development of embryonic tissues. We reported earlier that EGF-Rs are not expressed on the cell surface of undifferentiated embryonal carcinoma (EC) cells, but intracellular receptor protein is detectable (A. Weller, J. Meek, and E. D. Adamson, Development, 100: 351-363, 1987). We document here that in embryonal carcinoma cells, low levels of both receptor mRNA and protein are observed, but after 4 days of retinoic acid-induced differentiation, large increases are seen. Most notable is the 35-70-fold rise in the levels of EGF-R transcripts during the differentiation of P19 embryonal carcinoma cells to neural and glial cells, and this is paralleled by a 10-fold rise in protein. Measurements of the degradation rates of EGF-R mRNA and receptor protein show that both are rather stable and may partially explain the steady-state increases during differentiation. Run-on transcription assays of the EGF-R gene show very low rates of transcriptional activity at all stages: about 2-fold changes in transcription rate can be detected. It is concluded that transcriptional mechanisms may also partially account for increased levels of gene products. We hypothesize that the appearance of EGF-Rs at the cell surface leads to the slow induction of further receptor levels by EGF/transforming growth factor alpha stimulation, and this contributes to the driving force of differentiation and to the stability of the differentiated state.