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Modulating the activity of the c-Myc oncoprotein

implications for therapeutic treatment

Hydbring, Per (2009). Modulating the activity of the c-Myc oncoprotein. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis agriculturae Sueciae, 1652-6880 ; 2009:7
ISBN 978-91-86195-54-0
[Doctoral thesis]

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Abstract

The Myc oncoprotein regulates numerous cellular processes and is frequently deregulated in cancer due to genetic lesions. However, in addition to its tumor promoting activity, Myc and other oncoproteins induce intrinsic safe-guard mechanisms against tumorigenesis like apoptosis and cellular senescence, which have to be overcome by additional genetic lesions for cellular transformation. In this work, we identify ways of reactivating these anti-tumorigenic pathways in cells with deregulated Myc. First, we uncover an unexpected capacity of transforming growth factor-β (TGF-β) to force hematopoietic cells with deregulated Myc into cellular senescence despite continuous Myc expression. This involved upregulation of the Myc antagonist Mad1, leading to repressed transcription of Myc target genes. We further reveal a novel role of Myc in Myc/Ras dependent transformation. While Ras induced cellular senescence and suppressed Myc-activated apoptosis, we found that Myc repressed Ras-induced senescence. This required phosphorylation of Myc at Ser-62 by cyclin dependent kinase 2 (Cdk2). Further, pharmacological inhibitors of Cdk2 forced Myc+Ras expressing cells into senescence. In addition, although redundant for cell cycle progression, Cdk2 was shown to have a unique role in suppressing Myc-induced senescence, and depletion of Cdk2 in a mouse Eµ-myc lymphoma model led to regression of tumor development. Taken together, this highlights Cdk2-targeting in Myc and Ras-driven tumors. Finally, we uncover a novel interplay between Myc and the protein deacetylase SIRT1. While Myc induced SIRT1 expression and activity, SIRT1 fed back to Myc by stabilizing the Myc protein. Further, SIRT1 repressed Myc-induced apoptosis and senescence, pointing out SIRT1 as a promising target in neoplasia driven by Myc. In summary, this thesis demonstrates potential new strategies for therapeutic intervention of tumors with deregulated Myc by targeting its essential cofactors and collaboration partners.

Authors/Creators:Hydbring, Per
Title:Modulating the activity of the c-Myc oncoprotein
Subtitle:implications for therapeutic treatment
Year of publishing :2009
Volume:2009:7
Number of Pages:107
Papers/manuscripts:
NumberReferences
ALLI. Wu, S., Hultquist, A., Hydbring, P., Cetinkaya, C., Öberg, F., and Larsson, L.G. TGF-β induces senescence in Myc-transformed monocytic cells correlating with induction of Mad1 and repression of Myc-driven transcription (manuscript). II. Hydbring, P., Bahram, F., Su, Yingtao., Tronnersjö, S., Högstrand, K., von der Lehr, N., Lilischkis, R., Hein, N., Wu, S., Vervoorts, J., Henriksson, M., Grandien, A., Lüscher, B., and Larsson, L.G. Myc transforms by repressing Ras-induced senescence through Cdk2-mediated Ser-62 phosphorylation (manuscript). III. Campaner, S., Doni, M., Hydbring, P., Verrecchia, A., Bianchi, L., Sardella, D., Schleker, T., Perna, D., Tronnersjö, S., Barbacid, M., Larsson, L.G., and Amati, B. Cdk2 suppresses cellular senescence induced by the myc oncogene and oxidative stress (manuscript). IV. Menssen, A., Hydbring, P., Kapelle, K., Diebold, J., Bornkamm, G.W., Larsson, L.G., Lüscher, B., and Hermeking, H. Mutual regulation of c-MYC and SIRT1 constitutes a positive feed-back loop promoting cancer cell expansion (manuscript).
Place of Publication:Uppsala
ISBN for printed version:978-91-86195-54-0
ISSN:1652-6880
Language:English
Publication Type:Doctoral thesis
Full Text Status:Public
Agrovoc terms:transcription factors, transcription, mammals, cell cycle, senescence, transforming growth factor, interferons, phosphorylation, neoplasms, therapy
Keywords:Myc, cyclin E/Cdk2, p27Kip1, SIRT1, transforming growth factor-β, interferon-γ, cell cycle, cellular senescence, phosphorylation, SA-β-Gal
URN:NBN:urn:nbn:se:slu:epsilon-2731
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-2731
ID Code:1928
Department:(NL, NJ) > Dept. of Plant Biology and Forest Genetics (until 131231)
Deposited By: Per Hydbring
Deposited On:04 Feb 2009 00:00
Metadata Last Modified:02 Dec 2014 10:15

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