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Ubiquitin and proteasomes

Regulation of cellular polyamines by antizyme

Nature Reviews Molecular Cell Biology volume 2, pages 188–194 (2001)Cite this article

Abstract

Proteins that are degraded by the proteasome are first modified by a set of enzymes that attach multiple copies of ubiquitin to substrate lysines, but a tiny minority, including the polyamine-synthesizing enzyme ornithine decarboxylase, is handled differently. This enzyme is targeted for destruction by another protein ? antizyme. Why does ornithine decarboxylase have its own dedicated destruction mechanism, how does it work, and is it the only protein to be targeted to the proteasome in this way?

Key Points

  • Most cellular proteins are tagged for destruction by the proteasome through ubiquitylation. But a small minority, including the polyamine-synthesizing enzyme ornithine decarboxylase (ODC), has evolved distinct mechanisms ? in the case of ODC, it is antizyme.

  • The polyamines putrescine, spermidine and spermine are positively charged molecules that bind to DNA and RNA, so polynucleotide synthesis needs to be coordinated with polyamine synthesis. Mitogens therefore lead to a transient increase in polyamine biosynthesis. Mutations or drugs that reduce polyamine biosynthesis halt cell growth.

  • Spermidine is also crucial for the post-translational modification ? hypusination ? of the eukaryotic translation initiation factor 5A. Preventing hypusination leads to cell growth arrest.

  • It is also imperative to limit polyamine synthesis. Antizyme negatively regulates polyamines by inhibiting their production and their transport into cells. Antizyme production itself depends on polyamine levels, because the efficiency of the translational frameshifting process that mediates production of antizyme is increased by high levels of polyamines.

  • Antizyme binds to ODC with high affinity and disrupts active ODC homodimers. It then acts catalytically to direct the proteasome to destroy ODC.

  • Domain analysis indicates that both the carboxy-terminal region of ODC and the amino-terminal region of antizyme are needed for proteasomal degradation of ODC.

  • The prostate is the only vertebrate organ where polyamines are exported; most of the spermidine and spermine ends up in seminal fluid. Here, polyamines are proposed to hold prostate cells in G1 phase, through induction of antizyme.

  • Transgenic mice that overexpress ODC or antizyme in keratinocytes underline the importance of controlling polyamine levels to prevent the formation of skin cancers.

  • Vertebrates have at least three independently conserved antizyme isoforms. Whereas both AZ1 and AZ2 have a wide tissue distribution, AZ3 is testis-specific and is restricted to a late stage in sperm production.

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Figure 1: Biosynthesis and catabolism of polyamines.
Figure 2: The two-step enzymatic reaction that results in hypusination of a single lysine in eIF-5A.
Figure 3: Motifs in vertebrate antizymes that underlie translational frameshifting.
Figure 4: A regulatory feedback mechanism stabilizing polyamine pools.

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Acknowledgements

I am grateful to J. Atkins, D. Finley, S. Matsufuji, A. Pegg and B. Zetter for providing data before publication. The author's laboratory is supported, in part, by a National Institutes of Health grant.

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Authors and Affiliations

  1. Department of Microbiology and Immunology and Department of Medicine, University of California, San Francisco, San Francisco , 94143-0414, California, USA

    Philip Coffino

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  1. Philip Coffino
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Related links

Related links

DATABASE LINKS

Antizyme

orthinine decarboxylase

eIF-5A

cdk4

cyclin D1

spermidine/spermine acetyltransferase

AZ2

AZ3

FURTHER INFORMATION

Coffino lab

ENCYCLOPEDIA OF LIFE SCIENCES

Protease complexes

Glossary

HYPUSINATION

A post-translational modification thought to be unique to eukaryotic translation initiation factor 5A. An amino-butyl group is attached to lysine and then becomes hydroxylated to form a hypusyl group.

MITOGENS

Compounds that induce cell division.

FRAMESHIFT

All nucleic acids can be transcribed in three different frames, although generally only one frame is used. Frameshifting can be induced by removing or adding a nucleotide, or by frame slippage, to yield an RNA that encodes a different protein.

CYCLINS

A family of proteins whose levels fluctuate throughout the cell cycle. By activating cyclin-dependent kinases, they help to regulate several stages of cell division.

KERATINOCYTES

Differentiated epithelial cells of the skin.

HYPERTROPHY

An increase in the size of a tissue or organ that results from an increase in the size of cells present.

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Coffino, P. Regulation of cellular polyamines by antizyme. Nat Rev Mol Cell Biol 2, 188–194 (2001). https://doi.org/10.1038/35056508

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