Journal Article

Tumor suppressor activity of ODC antizyme in MEK-driven skin tumorigenesis

David J. Feith, Sofia Origanti, Paula L. Shoop, Suzanne Sass-Kuhn and Lisa M. Shantz

in Carcinogenesis

Volume 27, issue 5, pages 1090-1098
Published in print May 2006 | ISSN: 0143-3334
Published online January 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi343
Tumor suppressor activity of ODC antizyme in MEK-driven skin tumorigenesis

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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.

Keywords: AZ, antizyme; DFMO, α-difluoromethylornithine; DMBA, 7,12-dimethylbenz[a]anthracene; K5, keratin 5; K6, keratin 6; K14, keratin 14; MEK, mitogen-activated protein kinase kinase; ODC, ornithine decarboxylase; ORS, outer root sheath; TPA, tetradecanoyl phorbol acetate

Journal Article.  6915 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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