Increased expression of p50-NF-kappa B and constitutive activation of NF-kappa B transcription factors during mouse skin carcinogenesis

To elucidate the possible role of NF-kappa B in mouse skin carcinogenesis w e studied the expression of p50 (NF-kappa B1), p52 (NF-kappa B2), p65 (ReIA ) and I kappa B-alpha inhibitor as well as kappa B-binding activity in adul t SENCAR mouse skin, skin papillomas, and squamous cell carcinomas (SCC) ge nerated by a two-stage carcinogenesis protocol. We found that in normal epi dermis all of the above proteins were mostly expressed in the cytoplasm of basal cells. Western blot analysis revealed a dramatic increase of p50 and p52 expression in mouse skin tumors starting from the middle stage of promo tion. We also found that the level of I kappa B-alpha protein in many late papillomas and see was lower than in normal epidermis, Results of EMSA show ed an increase in kappa B-binding activity in mouse skin tumors and suggest ed that p50 is the major component of constitutive kappa B-binding complexe s in normal epidermis and in tumors. It has been shown that nuclear I kappa B protein Bcl-3 is able to increase p50/p50 homodimer binding to the diffe rent kappa B sites in mouse thymocytes. Our finding on Bcl-3 overexpression in late papillomas and SCC could explain the selective increase of p50-rel ated kappa B-binding in mouse skin tumors, Thus, our results strongly sugge st the important role of p50 in skin carcinogenesis.