Discordant transforming growth factor beta 1 RNA and protein localization during chemical carcinogenesis of the skin.
Transforming growth factor beta (TGF-beta) inhibits proliferation of normal keratinocytes, and this response is retained, to variable extents, in benign tumors of the skin (S. Haddow, D. J. Fowlis, K. Parkinson, R. J. Akhurst, and A. Balmain, Oncogene, 6: 1465-1470, 1991). To investigate the profile of TGF-beta biosynthesis during various stages of chemical carcinogenesis of the skin, we used a combination of ribonuclease protection assay, in situ hybridization with gene-specific probes for TGF-beta 1, -beta 2, and -beta 3, and immunohistochemistry with isoform-specific antibodies against TGF-beta 1. Following 12-O-tetradecanoylphorbol-13-acetate treatment of adult mouse skin, there was a rapid induction of TGF-beta 1 protein. Intracellular TGF-beta 1 protein was localized to suprabasal keratinocytes, and the extracellular form was localized predominantly to the dermis. Despite ubiquitous induction of TGF-beta 1 protein by 12-O-tetradecanoylphorbol-13-acetate in various mouse strains, we noted strain-specific differences in the quantitative induction of TGF-beta 1 RNA. Papillomas and carcinomas induced in vivo had elevated levels of TGF-beta 1 RNA within the basal keratinocyte compartment but did not contain significant levels of TGF-beta 1 protein within the tumor. We postulate that the tumor evades TGF-beta 1-controlled negative growth regulation by altered translational and/or posttranslational processing mechanisms of this growth factor. Levels of TGF-beta 2 and -beta 3 RNA were not elevated at any stage of chemical carcinogenesis of the skin.
Fowlis
D J
DJ
Duncan Guthrie Institute of Medical Genetics, University of Glasgow, Yorkhill Hospitals, United Kingdom.
Flanders
K C
KC
Duffie
E
E
Balmain
A
A
Akhurst
R J
RJ
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002277:Carcinoma / Q000139:chemically induced* / Q000378:metabolism; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D010212:Papilloma / Q000139:chemically induced* / Q000378:metabolism; D010703:Phorbol Esters; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics
D010703:Phorbol Esters; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D015127:9,10-Dimethyl-1,2-benzanthracene