umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Myc-induced Lymphomagenesis: In vivo assessment of downstream pathways
Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Myc-inducerad lymfomutveckling : Utvärdering av målgener in vivo (Swedish)
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.

Place, publisher, year, edition, pages
2010. , 79 p.
Keyword [en]
Myc, lymphomagenesis, Aurora kinases, polyamine, glycolysis, targeting, mouse models of cancer
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-32093ISBN: 978-91-7264-951-4 (print)OAI: oai:DiVA.org:umu-32093DiVA: diva2:300930
Public defence
2010-03-26, Building 6L, Major Groove, Umeå University, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2010-03-05 Created: 2010-03-01 Last updated: 2010-03-05Bibliographically approved
List of papers
1. Aurora kinases A and B are Myc targets essential for maintenance of the malignant state
Open this publication in new window or tab >>Aurora kinases A and B are Myc targets essential for maintenance of the malignant state
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-32092 (URN)
Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2010-03-02
2. Chemoprevention of B-cell lymphomas by inhibition of the Myc target spermidine synthase
Open this publication in new window or tab >>Chemoprevention of B-cell lymphomas by inhibition of the Myc target spermidine synthase
2010 (English)In: Cancer Prevention Research, ISSN 1940-6207, E-ISSN 1940-6215, Vol. 3, no 2, 140-147 p.Article in journal (Refereed) Published
Abstract [en]

The oncogenic transcription factor c-Myc (Myc) is frequently overexpressed in human cancers. Myc is known to induce or repress a large set of genes involved in cell growth and proliferation, explaining the selection for mutations in cancer that deregulate Myc expression. Inhibition of ornithine decarboxylase, an enzyme of the polyamine biosynthetic pathway and a Myc target, has been shown to be chemopreventive. In the present study, we have dissected the role of another enzyme in the polyamine biosynthetic pathway, spermidine synthase (Srm), in Myc-induced cancer. We find that Srm is encoded by a Myc target gene containing perfect E-boxes and that it is induced by Myc in a direct manner. RNA interference against Srm shows that it is important for Myc-induced proliferation of mouse fibroblasts but to a lesser extent for transformation. Using the compound trans-4-methylcyclohexylamine, we show that Srm inhibition can delay the onset of B-cell lymphoma development in λ-Myc transgenic mice. We therefore suggest that inhibition of Srm is an additional chemopreventive strategy that warrants further consideration.

Place, publisher, year, edition, pages
Philadelphia, PA: American Association for Cancer Research, 2010
Keyword
Myc, Srm, Odc, polyamines, lymphomagenesis
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-32085 (URN)10.1158/1940-6207.CAPR-09-0166 (DOI)000274247000005 ()
Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2017-12-12Bibliographically approved
3. Differential requirement of Ldha in Myc-induced tumorigenesis based on cooperating oncogenic lesion and tumor immunogenicity
Open this publication in new window or tab >>Differential requirement of Ldha in Myc-induced tumorigenesis based on cooperating oncogenic lesion and tumor immunogenicity
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-32091 (URN)
Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2011-09-06Bibliographically approved

Open Access in DiVA

fulltext(1205 kB)801 downloads
File information
File name FULLTEXT01.pdfFile size 1205 kBChecksum SHA-512
af79c06ccef0425168e07c7e12c57ca34e8031cd8cdb9877a54e6ea084f7ed6412f3c4d19e7d9dec44a95133f17cc3d722f6a698ac402bb98967d289057727e9
Type fulltextMimetype application/pdf

Search in DiVA

By author/editor
Rimpi, Sara
By organisation
Molecular Biology (Faculty of Science and Technology)
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 801 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 622 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf