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Teratocarcinoma cells provide us with a model system for the study of differentiation and development. One of the best characterized cell lines, the embryonal carcinoma stem cell line F9, differentiates after treatment with retinoic acid (RA) and dibutyryl cyclic AMP into parietal endoderm. This differentiation process is accompanied by the induction of several genes, for example, those encoding collagen IV, plasminogen activator and intermediate filaments like laminin. In contrast, a marked reduction of stable messenger RNA has been observed for the gene encoding p53 and for c-myc. Both cellular oncogenes seem to be involved in the regulation of cellular proliferation and neoplastic transformation. For growth-arrested 3T3 fibroblasts, growth-factor-induced changes of myc RNA are controlled at the level of transcription. In contrast, F9 cells provide a differentiation system in which cells are able to change from a tumorigenic state into non-dividing, non-tumorigenic endodermal cells. The latter process enabled us to study the regulation of myc and p53 genes in the same cells at different stages of growth, tumorigenicity and differentiation. Here we report that down-regulation of stable myc and p53 RNA during irreversible differentiation of F9 cells occurs at the post-transcriptional level. Using an in vitro nuclear transcription assay, we found that the polymerase II density on both genes remains constant during differentiation. In agreement with this interpretation, we detected myc RNA as stable transcripts in differentiated F9 cells after treatment of the cells with cycloheximide. The post-transcriptional regulatory mechanisms controlling p53 and myc stability follow different kinetics. Whereas the down-regulation of myc seems to be an early event of F9 differentiation occurring within the first 24 h, the post-transcriptional regulation of p53 occurs at a later stage (two to three days), possibly as a consequence of cell cycle changes.
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PMID:Post-transcriptional control of myc and p53 expression during differentiation of the embryonal carcinoma cell line F9. 241 65

EGF receptors are expressed on most fetal and adult cells but their precise roles are not well known. We previously reported that, in P19 embryonal carcinoma cells, the expression of kinase-negative EGFR inhibits retinoic acid (RA)-induced differentiation to nervous tissue, suggesting that EGFR plays a role in differentiation (J.-X. Wu and E. D. Adamson (1993) Dev. Biol. 159, 208-222). Embryo stem (ES) cells differentiate into a wide range of tissue types after the removal of the cytokine LIF from the culture medium. We demonstrate here that the induction of some early markers of differentiation, tissue-type plasminogen activator (tPA), AFP and keratins 8 and 19 is inhibited, whilst brachyury and myosin are increased, in clones containing kinase-negative mutant EGFR. After an extended period of differentiation, the cell types present in mutant and control cultures differed. Mutant clones produced frequent cardiac and skeletal muscle as the predominant differentiated cell types in vitro; other cells types were sparse or absent. Teratocarcinomas formed by EGFR-deltakinase-expressing ES cells contained frequent skeletal and cardiac muscle as well as apoptotic nuclei, while normal ES cells produced no detectable muscle and less apoptoses. Since mutant differentiated cultures had slower growth rates and increased levels of cell death, we concluded that: (1) inactive EGFR does not allow some cell types to survive and/or proliferate; (2) tissues that do not require EGFR for their survival, development or function predominate in long-term mutant cultures; (3) EGFR activity is not necessary for cardiac and skeletal muscle or endoderm formation and (4) Impaired survival of EGF-dependent lineages leads to preferential selection of muscle in differentiating ES cells.
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PMID:Kinase-negative mutant epidermal growth factor receptor (EGFR) expression during embryonal stem cell differentiation favours EGFR-independent lineages. 889 44