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Differential requirement of Ldha in Myc-induced tumorigenesis based on cooperating oncogenic lesion and tumor immunogenicity
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
Helmholtz Zentrum München, National Research Center for Environmental Health (GSF), Institute of Clinical Molecular Biology and Tumor Genetics, München, Germany. (Walter Pretsch)
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(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-32091OAI: oai:DiVA.org:umu-32091DiVA: diva2:300919
Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2011-09-06Bibliographically approved
In thesis
1. Myc-induced Lymphomagenesis: In vivo assessment of downstream pathways
Open this publication in new window or tab >>Myc-induced Lymphomagenesis: In vivo assessment of downstream pathways
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Myc-inducerad lymfomutveckling : Utvärdering av målgener in vivo
Abstract [en]

Myc oncogenes encode transcription factors that bind to E-box sequences in DNA, driving the expression of a large number of target genes and are deregulated in approximately 70% of human cancers. Deregulated Myc expression cause enhanced proliferation (which is counteracted by apoptosis), angiogenesis and cancer. Though Myc’s importance in induction of S phase has been established, less is known about its functions in the G2 and M phases of the cell cycle. Paper I addresses the targeting of the Myc targets Aurora kinase A and B that have roles in G2/M transition and provide evidence that pharmaceutical Aurora kinase inhibition causes cell cycle arrest and apoptosis in a Myc-selective manner and is useful in treating Myc-induced lymphomas in vivo.

The assumption that the important target genes responsible for the biological effects of Myc overexpression were those encoding components of the cell cycle machinery lead to little interest in other potentially important groups of target genes. However, recent work challenged this view by indicating that Myc target genes encoding metabolic enzymes may be critical for Myc-induced tumorigenesis. Importantly, the targeting of Myc target genes encoding metabolic enzymes has the potential of providing a new treatment strategy of Myc-induced cancers. Paper II covers the pharmaceutical targeting of the Myc-induced spermidine synthase (Srm) that shows promise as a tool for chemoprevention by affecting proliferation, but not for the treatment of established tumors.

Paper III focuses on the negligible effect an Ldha mutation has on Myc- induced lymphomagenesis. Ldha has long been known to be a Myc target gene and in vitro experiments have recently indicated it to be important for transformation. It seems the negligible effect of the Ldh mutation can be explained by the high frequency of loss of either Arf or p53 in this mouse model, since enforced Ras-Myc oncogenic cooperation in soft agar assays of Ldh mutant MEFs effectively inhibits colony formation, and λ-Myc;Ldh mutant bone marrow infected with oncogenic Ras does not give rise to tumors when transplanted into wild-type mice. A role for Ldh in the ability of tumors to evade the immune system was also indicated in this study. The combined experiences and very different outcome of the three studies included in this thesis draw attention to the value of in vivo assessment of Myc downstream targets in Myc-induced lymphomagenesis.

Publisher
79 p.
Keyword
Myc, lymphomagenesis, Aurora kinases, polyamine, glycolysis, targeting, mouse models of cancer
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-32093 (URN)978-91-7264-951-4 (ISBN)
Public defence
2010-03-26, Building 6L, Major Groove, Umeå University, Umeå, 10:00 (English)
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Available from: 2010-03-05 Created: 2010-03-01 Last updated: 2010-03-05Bibliographically approved

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Citation style
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