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. (July 2012) A tumour suppressor network relying on the polyamine-hypusine axis. Nature, 487 (7406). pp. 244-8. ISSN 1476-4687 (Electronic)0028-0836 (Linking)
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.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > suppressor |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Cancer Genetics CSHL Cancer Center Program > Signal Transduction CSHL Cancer Center Shared Resources > Proteomics Service CSHL labs > Krasnitz lab CSHL labs > Lowe lab CSHL labs > Pappin lab School of Biological Sciences > Publications CSHL Cancer Center Shared Resources > Mass Spectrometry Service |
| Depositing User: | Matt Covey |
| Date: | 12 July 2012 |
| Date Deposited: | 22 Jan 2013 15:57 |
| Last Modified: | 30 Oct 2015 14:43 |
| PMCID: | PMC3530829 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27040 |
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