A role for antizyme inhibitor in cell proliferation

Tania M Silva, Helena Cirenajwis, Heather M. Wallace, Stina Oredsson, Lo Persson

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Abstract

The polyamines are important for a variety of cellular functions, including cell growth. Their intracellular concentrations are controlled by a complex network of regulatory mechanisms, in which antizyme (Az) has a key role. Az reduces the cellular polyamine content by down-regulating both the enzyme catalysing polyamine biosynthesis, ornithine decarboxylase (ODC), and the uptake of polyamines. The activity of Az is repressed by the binding of a protein, named Az inhibitor (AzI), which is an enzymatically inactive homologue of ODC. Two forms of AzI have been described: AzI1, which is ubiquitous, and AzI2 which is expressed in brain and testis. In the present study, we have investigated the role of AzI1 in polyamine homeostasis and cell proliferation in breast cancer cells. The results obtained showed that the cellular content of AzI increased transiently after induction of cell proliferation by diluting cells in fresh medium. Inhibition of polyamine biosynthesis induced an even larger increase in the cellular AzI content, which remained significantly elevated during the 7-day experimental period. However, this increase was not a consequence of changes in cell cycle progression, as demonstrated by flow cytometry. Instead, the increase appeared to correlate with the cellular depletion of polyamines. Moreover, induced overexpression of AzI resulted in an increased cell proliferation with a concomitant increase in ODC activity and putrescine content. During mitosis, AzI1 was localised in a pattern that resembled that of the two centrosomes, confirming earlier observations. Taken together, the results indicate that AzI fulfils an essential regulatory function in polyamine homeostasis and cell proliferation.
Original languageEnglish
Pages (from-to)1341-1352
Number of pages12
JournalAmino Acids
Volume47
Issue number7
Early online date27 Mar 2015
DOIs
Publication statusPublished - Jul 2015

Fingerprint

Cell proliferation
Polyamines
Cell Proliferation
Ornithine Decarboxylase
Biosynthesis
Homeostasis
Cells
Centrosome
Putrescine
Flow cytometry
Complex networks
Cell growth
Mitosis
Testis
Brain
Cell Cycle
Carrier Proteins
Flow Cytometry
Breast Neoplasms
Enzymes

Keywords

  • antizyme inhibitor 1
  • polyamines
  • ornithine decarboxylase
  • cell proliferation
  • breast cancer

Cite this

Silva, T. M., Cirenajwis, H., Wallace, H. M., Oredsson, S., & Persson, L. (2015). A role for antizyme inhibitor in cell proliferation. Amino Acids, 47(7), 1341-1352. https://doi.org/10.1007/s00726-015-1957-6

A role for antizyme inhibitor in cell proliferation. / Silva, Tania M; Cirenajwis, Helena; Wallace, Heather M.; Oredsson, Stina; Persson, Lo.

In: Amino Acids, Vol. 47, No. 7, 07.2015, p. 1341-1352.

Research output: Contribution to journalArticle

Silva, TM, Cirenajwis, H, Wallace, HM, Oredsson, S & Persson, L 2015, 'A role for antizyme inhibitor in cell proliferation', Amino Acids, vol. 47, no. 7, pp. 1341-1352. https://doi.org/10.1007/s00726-015-1957-6
Silva TM, Cirenajwis H, Wallace HM, Oredsson S, Persson L. A role for antizyme inhibitor in cell proliferation. Amino Acids. 2015 Jul;47(7):1341-1352. https://doi.org/10.1007/s00726-015-1957-6
Silva, Tania M ; Cirenajwis, Helena ; Wallace, Heather M. ; Oredsson, Stina ; Persson, Lo. / A role for antizyme inhibitor in cell proliferation. In: Amino Acids. 2015 ; Vol. 47, No. 7. pp. 1341-1352.
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note = "Acknowledgments We thank Ewa Dahlberg and Lena Thiman for expert technical help with cell culturing and HPLC, respectively. The authors acknowledge financial support from the Portuguese Foundation for Science and Technology—SFRH/BD/46364/2008 (PhD fellowship to T. M. S.), the Gunnar Nilssons Cancer Foundation, the Mrs Berta Kamprad Foundation and the Per-Eric and Ulla Schyberg Foundation. Heather Wallace was supported by a visiting scholarship from Lund University. We are grateful for the generous supply of AzI antibody and pcDNA3.1-AzI from Dr. Senya Matsufuji and Dr. Yasuku Murakami (Tokyo, Japan), and Dr. Leif Andersson (Helsinki, Finland), respectively.",
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N1 - Acknowledgments We thank Ewa Dahlberg and Lena Thiman for expert technical help with cell culturing and HPLC, respectively. The authors acknowledge financial support from the Portuguese Foundation for Science and Technology—SFRH/BD/46364/2008 (PhD fellowship to T. M. S.), the Gunnar Nilssons Cancer Foundation, the Mrs Berta Kamprad Foundation and the Per-Eric and Ulla Schyberg Foundation. Heather Wallace was supported by a visiting scholarship from Lund University. We are grateful for the generous supply of AzI antibody and pcDNA3.1-AzI from Dr. Senya Matsufuji and Dr. Yasuku Murakami (Tokyo, Japan), and Dr. Leif Andersson (Helsinki, Finland), respectively.

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N2 - The polyamines are important for a variety of cellular functions, including cell growth. Their intracellular concentrations are controlled by a complex network of regulatory mechanisms, in which antizyme (Az) has a key role. Az reduces the cellular polyamine content by down-regulating both the enzyme catalysing polyamine biosynthesis, ornithine decarboxylase (ODC), and the uptake of polyamines. The activity of Az is repressed by the binding of a protein, named Az inhibitor (AzI), which is an enzymatically inactive homologue of ODC. Two forms of AzI have been described: AzI1, which is ubiquitous, and AzI2 which is expressed in brain and testis. In the present study, we have investigated the role of AzI1 in polyamine homeostasis and cell proliferation in breast cancer cells. The results obtained showed that the cellular content of AzI increased transiently after induction of cell proliferation by diluting cells in fresh medium. Inhibition of polyamine biosynthesis induced an even larger increase in the cellular AzI content, which remained significantly elevated during the 7-day experimental period. However, this increase was not a consequence of changes in cell cycle progression, as demonstrated by flow cytometry. Instead, the increase appeared to correlate with the cellular depletion of polyamines. Moreover, induced overexpression of AzI resulted in an increased cell proliferation with a concomitant increase in ODC activity and putrescine content. During mitosis, AzI1 was localised in a pattern that resembled that of the two centrosomes, confirming earlier observations. Taken together, the results indicate that AzI fulfils an essential regulatory function in polyamine homeostasis and cell proliferation.

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