uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
The Myc network of growth regulators and its interplay with growth and differentiation signals
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The proto-oncogenes/tumor suppressor genes of the Myc/N4ax/Mad network encode transcription factors that are important regulators of cell growth, differentiation, and apoptosis and that are frequently implicated in tumor development. Regulation of their biological functions by growth/differentiation signals as well as their interplay with growth/differentiation signalling pathways play important roles in cell fate determination. Elucidation of the underlying mechanisms, an issue addressed in this thesis, may not only increase our basic knowledge about eukaryotic growth regulation but may also contribute to novel therapeutic strategies for treatment of cancer.

Deregulated Myc expression blocks differentiation and anti-proliferative signals in a number of experimental systems. However, interferon-γ (IFN-γ) was shown to restore induced terminal differentiation of v-Myc-transformed U-937 human monoblasts. This thesis shows that several other cytokines, including interieukin-6 (IL-6), granulocyte/macrophage colony-stimulating factor (GM-CSF) and transforming growth factor β (TGF-β), also restore phorbol ester (TPA)-induced growth arrest and/or differentiation of these cells, despite continuous expression of v-Myc. Addressing the mechanism(s) behind the cytokine-induced anti-Myc activity, the thesis shows that TPA+IFN-γ treatment inhibits Myc-induced transcription and Mye DNA binding activity. This occurs through destabilisation of Myc's interaction with its essential partner Max, a mechanism correlated with post-translational modification of Myc by dephosphorylation. TGFβ treatment, in contrast, leads to up-regulation of the Myc antagonist, Mad1. The upregulation of Mad1 is correlated to increased Madl/Max complex formation and repression of Myc-dependent transcription.

The thesis further shows that Myc not only interferes with differentiation signals by activating target genes but also by repressing transcription of the cyclin-dependent kinase inhibitor p2lCIPl, a key regulator of the cell cycle, through a control region close to the transcriptional start site.

In conclusion, the thesis suggests that cytokine-induced signals can inhibit Myc function through direct posttranslational modification of Myc or alternatively through upregulation of its antagonist Mad1. On the other hand, Myc also interferes with differentiation signals by repressing inhibitors of cell cycle progression.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2000. , 74 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 982
Keyword [en]
Genetics, Myc, Mad1, p21Cip1, phorbol ester, IFN-g, TGF-b, differentiation
Keyword [sv]
National Category
Medical Genetics
Research subject
URN: urn:nbn:se:uu:diva-1259ISBN: 91-554-4894-1OAI: oai:DiVA.org:uu-1259DiVA: diva2:160820
Public defence
2001-01-13, The Rudbeck hall at the Dept. of Genetics and Pathology, Dag Hammarskjölds väg 20, Uppsala, Uppsala, 09:15
Available from: 2000-12-23 Created: 2000-12-23Bibliographically approved

Open Access in DiVA

No full text
Buy this publication >>

By organisation
Department of Genetics and Pathology
Medical Genetics

Search outside of DiVA

GoogleGoogle Scholar
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

Total: 79 hits
ReferencesLink to record
Permanent link

Direct link