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Stable siRNA-mediated silencing of antizyme inhibitor: regulation of ornithine decarboxylase activity.
Biochem Biophys Res Commun. 2005 Mar 04; 328(1):206-12.BB

Abstract

Ornithine decarboxylase (ODC) is the rate-limiting enzyme involved in the biosynthesis of polyamines essential for cell growth and differentiation. Aberrant upregulation of ODC, however, is widely believed to be a contributing factor in tumorigenesis. Antizyme is a major regulator of ODC, inhibiting ODC activity through the formation of complexes and facilitating degradation of ODC by the 26S proteasome. Moreover, the antizyme inhibitor (AZI) serves as another factor in regulating ODC, by binding to antizyme and releasing ODC from ODC-antizyme complexes. In our previous report, we observed elevated AZI expression in tumor specimens. Therefore, to evaluate the role of AZI in regulating ODC activity in tumors, we successfully down-regulated AZI expression using RNA interference technology in A549 lung cancer cells expressing high levels of AZI. Two AZI siRNAs, which were capable to generate a hairpin dsRNA loop targeting AZI, could successively decrease the expression of AZI. Using biological assays, antizyme activity increased in AZI-siRNA-transfected cells, and ODC levels and activity were reduced as well. Moreover, silencing AZI expression decreased intracellular polyamine levels, reduced cell proliferation, and prolonged population doubling time. Our results directly demonstrate that downregulation of AZI regulates ODC activity, intracellular polyamine levels, and cell growth through regulating antizyme activity. This study also suggests that highly expressed AZI may be partly responsible for increased ODC activity and cellular transformation.

Authors+Show Affiliations

Division of Metabolic Diseases, Department of Biomedical Sciences, National Institute of Health, #5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15670771

Citation

Choi, Kyoung Suk, et al. "Stable siRNA-mediated Silencing of Antizyme Inhibitor: Regulation of Ornithine Decarboxylase Activity." Biochemical and Biophysical Research Communications, vol. 328, no. 1, 2005, pp. 206-12.
Choi KS, Suh YH, Kim WH, et al. Stable siRNA-mediated silencing of antizyme inhibitor: regulation of ornithine decarboxylase activity. Biochem Biophys Res Commun. 2005;328(1):206-12.
Choi, K. S., Suh, Y. H., Kim, W. H., Lee, T. H., & Jung, M. H. (2005). Stable siRNA-mediated silencing of antizyme inhibitor: regulation of ornithine decarboxylase activity. Biochemical and Biophysical Research Communications, 328(1), 206-12.
Choi KS, et al. Stable siRNA-mediated Silencing of Antizyme Inhibitor: Regulation of Ornithine Decarboxylase Activity. Biochem Biophys Res Commun. 2005 Mar 4;328(1):206-12. PubMed PMID: 15670771.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stable siRNA-mediated silencing of antizyme inhibitor: regulation of ornithine decarboxylase activity. AU - Choi,Kyoung Suk, AU - Suh,Young Ho, AU - Kim,Won-Ho, AU - Lee,Tae Ho, AU - Jung,Myeong Ho, PY - 2004/11/24/received PY - 2005/1/27/pubmed PY - 2005/3/29/medline PY - 2005/1/27/entrez SP - 206 EP - 12 JF - Biochemical and biophysical research communications JO - Biochem. Biophys. Res. Commun. VL - 328 IS - 1 N2 - Ornithine decarboxylase (ODC) is the rate-limiting enzyme involved in the biosynthesis of polyamines essential for cell growth and differentiation. Aberrant upregulation of ODC, however, is widely believed to be a contributing factor in tumorigenesis. Antizyme is a major regulator of ODC, inhibiting ODC activity through the formation of complexes and facilitating degradation of ODC by the 26S proteasome. Moreover, the antizyme inhibitor (AZI) serves as another factor in regulating ODC, by binding to antizyme and releasing ODC from ODC-antizyme complexes. In our previous report, we observed elevated AZI expression in tumor specimens. Therefore, to evaluate the role of AZI in regulating ODC activity in tumors, we successfully down-regulated AZI expression using RNA interference technology in A549 lung cancer cells expressing high levels of AZI. Two AZI siRNAs, which were capable to generate a hairpin dsRNA loop targeting AZI, could successively decrease the expression of AZI. Using biological assays, antizyme activity increased in AZI-siRNA-transfected cells, and ODC levels and activity were reduced as well. Moreover, silencing AZI expression decreased intracellular polyamine levels, reduced cell proliferation, and prolonged population doubling time. Our results directly demonstrate that downregulation of AZI regulates ODC activity, intracellular polyamine levels, and cell growth through regulating antizyme activity. This study also suggests that highly expressed AZI may be partly responsible for increased ODC activity and cellular transformation. SN - 0006-291X UR - https://www.unboundmedicine.com/medline/citation/15670771/Stable_siRNA_mediated_silencing_of_antizyme_inhibitor:_regulation_of_ornithine_decarboxylase_activity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(04)02746-9 DB - PRIME DP - Unbound Medicine ER -