Differential regulation of transforming growth factor alpha autoinduction in a nontransformed and transformed epithelial cell.
Addition of transforming growth factor alpha (TGF-alpha) to cultured human keratinocytes results in enhanced expression of TGF-alpha mRNA. This phenomenon of TGF-alpha autoinduction is also observed in a TGF-alpha responsive colon cancer cell line, LIM 1215. In the present study, regulation of TGF-alpha autoinduction is examined in these two cell types. In human keratinocytes, but not in LIM 1215 cells, the increase in steady-state TGF-alpha mRNA following administration of TGF-alpha is due to stabilization of the 4.8-kilobase TGF-alpha transcript, as determined by actinomycin D decay curves. Nuclear run-on experiments confirmed transcriptional control in LIM 1215 cells. Basal and TGF-alpha-stimulated TGF-alpha expression is mediated, at least in part, through a protein kinase C-dependent pathway in both cell types, as determined by the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), which attenuates TGF-alpha mRNA accumulation. In the keratinocytes, but not in the LIM 1215 cells, basal TGF-alpha expression is mediated through an epidermal growth factor receptor-dependent pathway, as determined by antibody blockade of the epidermal growth factor receptor. Thus, differential regulation of TGF-alpha autoinduction exists in these nontransformed and transformed epithelial cell types.
Coffey
R J
RJ
Department of Medicine and Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Graves-Deal
R
R
Dempsey
P J
PJ
Whitehead
R H
RH
Pittelkow
M R
MR
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002461:Cell Line, Transformed / Q000737:chemistry / Q000187:drug effects; D003106:Colon / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D015603:Keratinocytes / Q000737:chemistry / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects*; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000494:pharmacology*
D007546:Isoquinolines; D010879:Piperazines; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C