Activation of ras oncogenes in chemically transformed BALB/MK‐2 mouse keratinocytes

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Abstract
BALB/MK‐2 cells are an epidermal growth factor (EGF)‐dependent cell line derived from BALB/c mouse epidermis that can undergo terminal differentiation under appropriate conditions. Previous studies have shown that transformation of these cells by retroviral oncogenes relieves the EGF requirement while blocking the terminal differentiation program. In this report we show that BALB/MK‐2 cells are sensitive to transformation by the chemical carcinogens dimethylbenz[a]anthracene (DMBA), 3‐methylcholanthrene (MCA), and N‐methyl‐N‐nitro‐N‐nitrosoguanidine (MNNG). BALB/MK‐2 cells transformed by these carcinogens proliferate in the absence of EGF and do not undergo terminal differentiation in response to calcium. However, the cells retain their anchorage growth dependence and are nontumorigenic in nude mice. NIH 3T3 transfection analysis showed that the endogenous Ha‐ras gene had been activated in both DMBA‐ and MNNG‐transformed cells and the Ki‐ras gene had been activated in the MCA‐transformed cells. Additionally, non‐ras transforming activity was detected in some MNNG‐transformed BALB/MK‐2 cells. Thus, the BALB/MK‐2 cell line provides a reproducible in vitro assay system for chemical transformation of epithelial cells and for identification of oncogene activations associated with changes in growth control and differentiation.