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Up-Regulation of c-myc in a Transformed Cell Line Approaching Stationary Phase Growth in Culture¹

Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030

The present report describes a transformed cell line (AKR-MCA) in which the c-myc proto-oncogene is up-regulated by as much as 14-fold as cultures approach stationary phase growth. The untransformed counterpart AKR-2B cells did not exhibit such an increase in c-myc expression at high cell densities, nor did chemically transformed derivatives of another murine fibroblast cell line (C3H 10T1/2). N,N-Dimethylformamide and retinoic acid reduced c-myc levels in confluent AKR-MCA cells in association with a loss of transformed morphology, a reduction in saturation density, and the formation of a contact-inhibited monolayer at confluency. These findings suggest that the high levels of c-myc in confluent AKR-MCA cells may interfere with the normal signals involved in density-dependent growth regulation in this cell system. The effects of N,N-dimethylformamide and retinoic acid were reversible and dose-related. The half-time for the early, rapid decline in c-myc mRNA was approximately 26 min in response to N,N-dimethylformamide and 38 min in response to retinoic acid, effects which preceded the alterations in morphology and saturation densities.

Activation of the latent transforming growth factor-ß in serum-free medium conditioned by confluent AKR-MCA cells, followed by its addition to preconfluent AKR-MCA cells, resulted in an up-regulation of c-myc mRNA. However, addition of serum-containing conditioned medium under similar conditions did not require prior acidification to up-regulate c-myc. Thus, active transforming growth factor-ß may be present in conditioned medium from confluent AKR-MCA cells grown in serum-containing medium, or autocrine factors other than TGF-ß may produce the confluency-associated up-regulation of c-myc and the altered density-dependent growth regulation in AKR-MCA cells.

¹ Supported by NIH Grant CA38173 from the National Cancer Institute.

² To whom requests for reprints should be addressed at, Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.

Received 9/ 1/87. Revised 11/23/88. Accepted 1/24/89.