MKK4 is required for skin tumor formation. mkk4skin+/+ and mkk4skin−/− animals were treated with DMBA/TPA. Controls correspond to age matched untreated mkk4skin+/+ mice. A, Representative picture of mice bearing papillomas 20 weeks after TPA treatment. B, Papillomas on the back skin of the mice were counted. The data, expressed as the mean +/− standard error (SE), were generated from three independent experiments (n = 10). C, H&E staining of sections of skin biopsies 20 weeks after TPA treatment demonstrates that DMBA/TPA treatment significantly increases the thickness of the epidermis of mkk4skin+/+, but not that of mkk4skin−/−, animals. Concomitantly, the loss of MKK4 prevents the expansion of a population of epithelial cells expressing the progenitor cell marker K6 as demonstrated by immunostaining with a specific antibody to K6. Scale bar represents 50 μM.