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  • 1
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    A tumour suppressor network relying on the polyamine-hypusine axis (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-06-23
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530829/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530829/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scuoppo, Claudio -- Miething, Cornelius -- Lindqvist, Lisa -- Reyes, Jose -- Ruse, Cristian -- Appelmann, Iris -- Yoon, Seungtai -- Krasnitz, Alexander -- Teruya-Feldstein, Julie -- Pappin, Darryl -- Pelletier, Jerry -- Lowe, Scott W -- CA087497/CA/NCI NIH HHS/ -- CA148532/CA/NCI NIH HHS/ -- MOP-106530/Canadian Institutes of Health Research/Canada -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA087497/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jul 12;487(7406):244-8. doi: 10.1038/nature11126.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Watson School of Biological Sciences, Cold Spring Harbor Laboratory, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722845" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Gene Deletion ; Gene Regulatory Networks ; Genetic Testing ; Humans ; Lymphoma, B-Cell/*genetics/physiopathology ; Lysine/*analogs & derivatives/chemistry ; Mice ; Mice, Inbred C57BL ; Polyamines/*chemistry ; RNA, Small Interfering/genetics/metabolism ; Reproducibility of Results ; Tumor Suppressor Proteins/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    PTEN action in leukaemia dictated by the tissue microenvironment (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-05-09
    Description: PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing. PTEN dephosphorylates phosphatidylinositol (3,4,5)-triphosphate, thereby opposing the activity of class I phosphatidylinositol 3-kinases that mediate growth- and survival-factor signalling through phosphatidylinositol 3-kinase effectors such as AKT and mTOR. To determine whether continued PTEN inactivation is required to maintain malignancy, here we generate an RNA interference-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal Pten knockdown in the haematopoietic compartment produced highly disseminated T-cell acute lymphoblastic leukaemia. Notably, reactivation of PTEN mainly reduced T-cell leukaemia dissemination but had little effect on tumour load in haematopoietic organs. Leukaemia infiltration into the intestine was dependent on CCR9 G-protein-coupled receptor signalling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, G-protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165899/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165899/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miething, Cornelius -- Scuoppo, Claudio -- Bosbach, Benedikt -- Appelmann, Iris -- Nakitandwe, Joy -- Ma, Jing -- Wu, Gang -- Lintault, Laura -- Auer, Martina -- Premsrirut, Prem K -- Teruya-Feldstein, Julie -- Hicks, James -- Benveniste, Helene -- Speicher, Michael R -- Downing, James R -- Lowe, Scott W -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA087497/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA045508/CA/NCI NIH HHS/ -- S10 OD016282/OD/NIH HHS/ -- U01 CA105388/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 19;510(7505):402-6. doi: 10.1038/nature13239. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [3] Department of Medicine I, Medical Center - University of Freiburg, 79106 Freiburg, Germany. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Howard Hughes Medical Institute, New York, New York 10065, USA. ; Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria. ; Departments of Anesthesiology and Radiology, Stony Brook University, Stony Brook, New York 11794, USA. ; 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [3] Howard Hughes Medical Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805236" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chemokines/metabolism ; Gene Knockdown Techniques ; Leukemia/*enzymology/genetics/*physiopathology ; Mice, Transgenic ; PTEN Phosphohydrolase/*genetics/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; RNA Interference ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; Tumor Microenvironment/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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