Increased expression of p50-NF-kappaB and constitutive activation of NF-kappaB transcription factors during mouse skin carcinogenesis.
To elucidate the possible role of NF-kappaB in mouse skin carcinogenesis we studied the expression of p50 (NF-kappaB1), p52 (NF-kappaB2), p65 (RelA) and IkappaB-alpha inhibitor as well as kappaB-binding activity in adult SENCAR mouse skin, skin papillomas, and squamous cell carcinomas (SCC) generated by a two-stage carcinogenesis protocol. We found that in normal epidermis 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 promotion. We also found that the level of IkappaB-alpha protein in many late papillomas and SCC was lower than in normal epidermis. Results of EMSA showed an increase in kappaB-binding activity in mouse skin tumors and suggested that p50 is the major component of constitutive kappaB-binding complexes in normal epidermis and in tumors. It has been shown that nuclear IkappaB protein Bcl-3 is able to increase p50/p50 homodimer binding to the different kappaB sites in mouse thymocytes. Our finding on Bcl-3 overexpression in late papillomas and SCC could explain the selective increase of p50-related kappaB-binding in mouse skin tumors. Thus, our results strongly suggest the important role of p50 in skin carcinogenesis.
Budunova
I V
IV
AMC Cancer Research Center, 1600 Pierce Street, Denver, Colorado, CO 80214, USA.
Perez
P
P
Vaden
V R
VR
Spiegelman
V S
VS
Slaga
T J
TJ
Jorcano
J L
JL
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D002273:Carcinogens; D004817:Epidermis / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018632:Mice, Inbred SENCAR; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate; D051996:Transcription Factor RelA; D014157:Transcription Factors
D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D002273:Carcinogens; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate