Induction of ornithine decarboxylase activity is a necessary step for mitogen-activated protein kinase kinase-induced skin tumorigenesis.
A transgenic mouse line overexpressing a constitutively active mutant of MEK1, a downstream effector of Ras, driven by the keratin 14 (K14) promoter, has been used to test the hypothesis that ornithine decarboxylase (ODC) induction during tumor promotion following a single initiating event [i.e., the activation of the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway], is a necessary step in skin carcinogenesis. K14-MEK mice exhibit moderate hyperplasia, with spontaneous skin tumor development within 5 weeks of birth. Analysis of epidermis and dermis showed induction of MEK protein and ERK1/ERK2 phosphorylation, but no change in Akt-1, suggesting that the PI 3-kinase pathway, another pathway downstream of ras, is not activated. Examination of tumors revealed high levels of ODC protein and activity, indicating that activation of signaling cascades dependent on MEK activity is a sufficient stimulus for ODC induction. When K14-MEK mice were given alpha-difluoromethylornithine (DFMO), a suicide inactivator of ODC, in the drinking water from birth, there was a dramatic delay in the onset of tumor growth ( approximately 6 weeks), and only 25% of DFMO-treated mice developed tumors by 15 weeks of age. All untreated K14-MEK mice developed tumors by 6 weeks of age. Treatment of tumor-bearing mice with DFMO reduced both tumor size and tumor number within several weeks. Tumor regression was the result of both inhibition of proliferation and increased apoptosis in tumors. The results establish ODC activation as an important component of the Raf/MEK/ERK pathway, and identify K14-MEK mice as a valuable model with which to study the regulation of ODC in ras carcinogenesis.
Feith
David J
DJ
Department of Cellular and Molecular Physiology, The Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Bol
David K
DK
Carboni
Joan M
JM
Lynch
Mark J
MJ
Sass-Kuhn
Suzanne
S
Shoop
Paula L
PL
Shantz
Lisa M
LM
D000818:Animals; D000518:Eflornithine / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D048369:MAP Kinase Kinase 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000096:biosynthesis* / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011247:Pregnancy; D012867:Skin / Q000201:enzymology / Q000473:pathology; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control
D065108:Ornithine Decarboxylase Inhibitors; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D009955:Ornithine Decarboxylase; D000518:Eflornithine