A tumour suppressor network relying on the polyamine–hypusine axis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-07

AUTHORS

Claudio Scuoppo, Cornelius Miething, Lisa Lindqvist, José Reyes, Cristian Ruse, Iris Appelmann, Seungtai Yoon, Alexander Krasnitz, Julie Teruya-Feldstein, Darryl Pappin, Jerry Pelletier, Scott W. Lowe

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. More... »

PAGES

244

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature11126

DOI

http://dx.doi.org/10.1038/nature11126

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1011169792

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22722845


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