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.

Keywords

transcription factors; transcription; mammals; cell cycle; senescence; transforming growth factor; interferons; phosphorylation; neoplasms; therapy

Published in

Acta Universitatis Agriculturae Sueciae
2009, number: 2009:7
ISBN: 9789186195540
Publisher: Dept. of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences

SLU Authors

• Hydbring, Per

  • Department of Plant Biology, Swedish University of Agricultural Sciences
    

UKÄ Subject classification

Cell Biology


Permanent link to this page (URI)

https://res.slu.se/id/publ/22771