title: Tumor suppressor activity of ODC antizyme in MEK-driven skin tumorigenesis.
abstract: To test the hypothesis that suppression of ornithine decarboxylase (ODC) activity blocks the promotion of target cells in the outer root sheath of the hair follicle initiated by Raf/MEK/ERK activation, we crossed mice overexpressing an activated MEK mutant in the skin (K14-MEK mice) with two transgenic lines overexpressing antizyme (AZ), which binds to ODC and targets it for degradation. K14-MEK mice develop spontaneous skin tumors without initiation or promotion. These mice on the ICR background were crossed with K5-AZ and K6-AZ mice on both the carcinogenesis-resistant C57BL/6 background and the sensitive DBA/2 background. Expression of AZ driven by either the K5 or K6 promoter along with K14-MEK dramatically delayed tumor incidence and reduced tumor multiplicity on both backgrounds compared with littermates expressing the MEK transgene alone. The effect was most remarkable in the MEK/K6-AZ mice from the ICR/D2 F1 cross, where double transgenic mice averaged less than one tumor per mouse for more than 8 weeks, while K14-MEK mice averaged over 13 tumors per mouse at this age. Putrescine was decreased in MEK/AZ tumors, while spermidine and spermine levels were unaffected, suggesting that the primary role played by AZ in this system is to inhibit putrescine accumulation. MEK/AZ tumors did not show evidence of apoptosis, but there was a 15-20% decrease in S-phase cells and a 40-60% decrease in mitotic cells in MEK/AZ tumors. These results indicate that the principal effect of AZ may be to slow cell growth primarily by increasing G2/M transit time.
authors.affiliation: Department of Cellular and Molecular Physiology, The Milton S. Hershey Medical Center, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Feith
authors.forename: Sofia
authors.initials: S
authors.lastname: Origanti
authors.forename: Paula L
authors.initials: PL
authors.lastname: Shoop
authors.forename: Suzanne
authors.initials: S
authors.lastname: Sass-Kuhn
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shantz
mesh_terms: D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation; D011506:Proteins / Q000494:pharmacology*; D011700:Putrescine / Q000494:pharmacology; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology*; D019076:Transgenes
chemical_list: D011506:Proteins; C031017:ornithine decarboxylase antizyme; D020930:MAP Kinase Kinase Kinases; D011700:Putrescine