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Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions.
Oncogene. 2006 Aug 24; 25(37):5163-72.O

Abstract

Antizyme inhibitor (AzI) is a homolog of ornithine decarboxylase (ODC), a key enzyme of polyamine synthesis. Antizyme inhibitor retains no enzymatic activity, but exhibits high affinity to antizyme (Az), a negative regulator of polyamine homeostasis. As polyamines are involved in maintaining cellular proliferation, and since AzI may negate Az functions, we have investigated the role of AzI in regulating cell growth. We show here that overexpression of AzI in NIH3T3 cells increased growth rate, enabled growth in low serum, and permitted anchorage-independent growth in soft agar, while reduction of AzI levels by AzI siRNA reduced cellular proliferation. Moreover, AzI overproducing cells gave rise to tumors when injected into nude mice. AzI overexpression resulted in elevation of ODC activity and of polyamine uptake. These effects of AzI are a result of its ability to neutralize Az, as overexpression of an AzI mutant with reduced Az binding failed to alter cellular polyamine metabolism and growth properties. We also demonstrate upregulation of AzI in Ras transformed cells, suggesting its relevance to some naturally occurring transformations. Finally, increased uptake activity rendered AzI overproducing and Ras-transformed cells more sensitive to toxic polyamine analogs. Our results therefore imply that AzI has a central and meaningful role in modulation of polyamine homeostasis, and in regulating cellular proliferation and transformation properties.

Authors+Show Affiliations

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16568078

Citation

Keren-Paz, A, et al. "Overexpression of Antizyme-inhibitor in NIH3T3 Fibroblasts Provides Growth Advantage Through Neutralization of Antizyme Functions." Oncogene, vol. 25, no. 37, 2006, pp. 5163-72.
Keren-Paz A, Bercovich Z, Porat Z, et al. Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions. Oncogene. 2006;25(37):5163-72.
Keren-Paz, A., Bercovich, Z., Porat, Z., Erez, O., Brener, O., & Kahana, C. (2006). Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions. Oncogene, 25(37), 5163-72.
Keren-Paz A, et al. Overexpression of Antizyme-inhibitor in NIH3T3 Fibroblasts Provides Growth Advantage Through Neutralization of Antizyme Functions. Oncogene. 2006 Aug 24;25(37):5163-72. PubMed PMID: 16568078.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions. AU - Keren-Paz,A, AU - Bercovich,Z, AU - Porat,Z, AU - Erez,O, AU - Brener,O, AU - Kahana,C, Y1 - 2006/03/27/ PY - 2006/3/29/pubmed PY - 2006/9/29/medline PY - 2006/3/29/entrez SP - 5163 EP - 72 JF - Oncogene JO - Oncogene VL - 25 IS - 37 N2 - Antizyme inhibitor (AzI) is a homolog of ornithine decarboxylase (ODC), a key enzyme of polyamine synthesis. Antizyme inhibitor retains no enzymatic activity, but exhibits high affinity to antizyme (Az), a negative regulator of polyamine homeostasis. As polyamines are involved in maintaining cellular proliferation, and since AzI may negate Az functions, we have investigated the role of AzI in regulating cell growth. We show here that overexpression of AzI in NIH3T3 cells increased growth rate, enabled growth in low serum, and permitted anchorage-independent growth in soft agar, while reduction of AzI levels by AzI siRNA reduced cellular proliferation. Moreover, AzI overproducing cells gave rise to tumors when injected into nude mice. AzI overexpression resulted in elevation of ODC activity and of polyamine uptake. These effects of AzI are a result of its ability to neutralize Az, as overexpression of an AzI mutant with reduced Az binding failed to alter cellular polyamine metabolism and growth properties. We also demonstrate upregulation of AzI in Ras transformed cells, suggesting its relevance to some naturally occurring transformations. Finally, increased uptake activity rendered AzI overproducing and Ras-transformed cells more sensitive to toxic polyamine analogs. Our results therefore imply that AzI has a central and meaningful role in modulation of polyamine homeostasis, and in regulating cellular proliferation and transformation properties. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/16568078/Overexpression_of_antizyme_inhibitor_in_NIH3T3_fibroblasts_provides_growth_advantage_through_neutralization_of_antizyme_functions_ L2 - http://dx.doi.org/10.1038/sj.onc.1209521 DB - PRIME DP - Unbound Medicine ER -