title: Systemic overexpression of antizyme 1 in mouse reduces ornithine decarboxylase activity without major changes in tissue polyamine homeostasis.
abstract: Polyamines, spermidine, spermine and their precursor putrescine, are ubiquitous cell components essential for normal cell growth. Increased polyamine levels and enhanced biosynthesis have been associated with malignant transformation and tumor formation, and thus, the polyamines have been considered to be a meaningful target to cancer therapies. However, clinical cancer treatment trials using inhibitors of polyamine synthesis have been unsuccessful probably due to compensatory uptake of polyamines from extracellular sources. The antizyme proteins regulate both polyamine biosynthesis and transport, and thus, the antizymes could provide an efficient approach to control cellular proliferation compared to the mere inhibition of biosynthesis. To define the role of antizymes in proliferative processes associated with the whole animal, we have generated transgenic mice overexpressing mouse antizyme 1 gene under its own regulatory sequences. Antizyme 1 protein was abundantly expressed in various organs and the expressed antizyme protein was functional as ornithine decarboxylase activity was significantly reduced in all tissues analyzed. However, antizyme 1 overexpression caused only minor changes in tissue polyamine levels demonstrating the challenges in using the "antizyme approach" to deplete polyamines in a living animal. Neither were there any changes in cellular proliferation in the proliferative tissues of transgenic animals. Interestingly though, there was occurrence of abnormally high level of apoptosis in the non-proliferating part of the colon epithelia. Otherwise, the transgenic founder mice appeared healthy and out of seven founders six were fertile. However, none of the founders could transmit the transgene suggesting that the antizyme 1 overexpression may be deleterious to transgenic gametes.
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, P.O.B 1627, 70211, Kuopio, Finland, Marko.Pietila@uef.fi.
authors.forename: Marko
authors.initials: M
authors.lastname: Pietilä
authors.forename: Hiramani
authors.initials: H
authors.lastname: Dhungana
authors.forename: Anne
authors.initials: A
authors.lastname: Uimari
authors.forename: Reijo
authors.initials: R
authors.lastname: Sironen
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005786:Gene Expression Regulation; D006706:Homeostasis; D051379:Mice; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D011073:Polyamines / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D011073:Polyamines; D011506:Proteins; C031017:ornithine decarboxylase antizyme; D009955:Ornithine Decarboxylase