A tumour suppressor network relying on the polyamine-hypusine axis Journal Article
| Authors: | Scuoppo, C.; Miething, C.; Lindqvist, L.; Reyes, J.; Ruse, C.; Appelmann, I.; Yoon, S.; Krasnitz, A.; Teruya-Feldstein, J.; Pappin, D.; Pelletier, J.; Lowe, S. W. |
| Article Title: | A tumour suppressor network relying on the polyamine-hypusine axis |
| Abstract: | Tumour suppressor genes encode a broad class of molecules whose mutational attenuation contributes to malignant progression. In the canonical situation, the tumour suppressor is completely inactivated through a two-hit process involving a point mutation in one allele and chromosomal deletion of the other. Here, to identify tumour suppressor genes in lymphoma, we screen a short hairpin RNA library targeting genes deleted in human lymphomas. We functionally identify those genes whose suppression promotes tumorigenesis in a mouse lymphoma model. Of the nine tumour suppressors we identified, eight correspond to genes occurring in three physically linked 'clusters', suggesting that the common occurrence of large chromosomal deletions in human tumours reflects selective pressure to attenuate multiple genes. Among the new tumour suppressors are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, we establish the polyamine-hypusine axis as a new tumour suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas and co-suppression of both genes promotes lymphomagenesis in mice. Thus, some tumour suppressor functions can be disabled through a two-step process targeting different genes acting in the same pathway. © 2012 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | controlled study; unclassified drug; gene cluster; human cell; gene deletion; nonhuman; reproducibility of results; chromosome; mouse; metabolism; animals; mice; mus; apoptosis; gene expression; animal experiment; animal model; rna, small interfering; enzyme activity; molecular library; cell line, tumor; mice, inbred c57bl; carcinogenesis; tumor suppressor gene; lymphoma, b-cell; eukaryota; public health; gene repression; tumor suppressor proteins; lymphoma; molecular analysis; amino acid; rodent; tumor; disease models, animal; chromosome deletion; short hairpin rna; lysine; genetic testing; gene regulatory networks; carboxylyase; polyamine; polyamines; adenosylmethionine decarboxylase 1; hypusine; initiation factor 5a; polyamine metabolism |
| Journal Title: | Nature |
| Volume: | 487 |
| Issue: | 7406 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2012-07-12 |
| Start Page: | 244 |
| End Page: | 248 |
| Language: | English |
| DOI: | 10.1038/nature11126 |
| PROVIDER: | scopus |
| PUBMED: | 22722845 |
| PMCID: | PMC3530829 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 1 August 2012" - "CODEN: NATUA" - "Source: Scopus" |
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