Protein kinase Cdelta-mediated signal to ornithine decarboxylase induction is independent of skin tumor suppression.
Protein Kinase Cdelta (PKCdelta), a Ca(2+)-independent, phospholipid-dependent serine/threonine kinase, is among the PKC isoforms expressed in mouse epidermis. We reported that FVB/N transgenic mice that overexpress ( approximately eightfold) PKCdelta protein in basal epidermal cells are resistant to skin tumor formation by the 7,12-dimethylbenz(a)anthracene (DMBA)-initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotion protocol. However, despite being resistant to skin tumor promotion by TPA, PKCdelta transgenic mice elicited a 3-4-fold increase in TPA-induced epidermal ODC activity and putrescine levels than their wild-type littermates. PKCdelta was observed to be the key component of the TPA signal transduction pathways to the induction of mouse epidermal ODC activity. To determine if TPA-induced ODC activity and associated putrescine levels in PKCdelta transgenic mice contributed to PKCdelta-mediated suppression of skin tumor promotion by TPA, the irreversible inhibitor of ODC, alpha-difluoromethylornithine (DFMO), was used. PKCdelta transgenic mice and their wild-type littermates were initiated with 100 nmol DMBA and then promoted twice weekly with 5 nmol TPA. The experimental group was given 0.5% DFMO in their drinking water, while the control group was given tap water. After 25 weeks, the number of papillomas (>2 mm) per mouse was counted. The DFMO treatment did not affect the skin tumor multiplicity of PKCdelta transgenic mice. These results indicate that PKCdelta-induced ODC activity is not involved in PKCdelta-mediated tumor suppression. Thus, the signaling pathways via PKCdelta to epidermal ODC induction and skin tumor suppression appear to be independent.
Wheeler
Deric L
DL
Department of Human Oncology, Medical School, University of Wisconsin, Madison, Wisconsin, WI 53792, USA.
Reddig
Peter J
PJ
Dreckschmidt
Nancy E
NE
Leitges
Michael
M
Verma
Ajit K
AK
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000037:antagonists & inhibitors; D000818:Animals; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D000518:Eflornithine / Q000494:pharmacology; D004789:Enzyme Activation; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004817:Epidermis / Q000201:enzymology / Q000473:pathology; D005260:Female; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D051745:Protein Kinase C-delta; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000502:physiology
D002273:Carcinogens; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D065108:Ornithine Decarboxylase Inhibitors; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate; D000518:Eflornithine