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Regulation and function of the Mad/Max/Myc network during neuronal and hematopoietic differentiation
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Mad/Max/Myc transcription factor network takes part in the control of vital cellular functions such as growth, proliferation, differentiation and apoptosis. Dimerization with the protein Max is necessary for the Myc-family of oncoproteins and their antagonists, the Mad-family proteins, to regulate target genes and carry out their intended functions. Myc functions as a positive regulator of proliferation, antagonized by the growth inhibitory Mad-proteins that potentially functions as tumor supprerssors. Deregulated Myc expression is found in a variety of tumors and signals negatively regulating Myc expression and/or activity could therefore be of potential use in treating tumors with deregulated Myc.

Our aim was to therefore to investigate possible negative effects on Myc expression and activity by growth inhibitory cytokines and by the Myc antagonists, the Mad-family proteins.Two different cellular model systems of neuronal and hematopoietic origin have been utilized for these studies.

Our results show that Mad1 is upregulated during induced neuronal differentiation of SH-SY5Y cells. Further, the growth inhibitory cytokine interferon-g (IFN-g) was shown to cooperate with retinoic acid (RA) and the phorbol ester TPA in inducing growth arrest and differentiation in N-myc amplified neuroblastoma cell lines. In contrast to treatment with either agent alone, the combined treatment of TPA+IFN-g and RA+IFN-g led to upregulation of Mad1 and to downregulation of N-Myc, respectively, thus correlating with the enhanced growth inhibition and differentiation observed after combination treatment. Ectopic expression of an inducible Mad1 in monoblastic U-937 cells led to growth inhibition but did not lead to differentiation or enhancement of differentiation induced by RA, vitamin D3 or TPA. In v-Myc transformed U-937 cells Mad1 expression reestablished the TPA-induced G1 cell cycle arrest, but did not restore differentiation, blocked by v-Myc. The growth inhibitory cytokine TGF-b was found to induce Mad1 expression and Mad1:Max complex formation in v-Myc transformed U-937 cells correlating with reduced Myc activity and G1 arrest.

In conclusion, our results show that the Myc-antagonist Mad1 is upregulated by growth inhibitory cytokines and/or differentiation signals in neuronal and hematopoietic cells and that enforced Mad1 expression in hematopoietic cells results in growth inhibition and increased sensitivity to anti-proliferative cytokines. Mad1 and cytokine-induced signals therefore seem to cooperate in counteracting Myc activity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2001. , p. 66
Keywords [en]
Genetics, Myc, Mad1, neuroblastoma, hematopoiesis, phorbol ester, retinoic acid, interferon-g, TGF-b, differentiation.
Keywords [sv]
Genetik
National Category
Medical Genetics
Research subject
Pathology
Identifiers
URN: urn:nbn:se:uu:diva-696ISBN: 91-554-5070-9 (print)OAI: oai:DiVA.org:uu-696DiVA, id: diva2:168566
Public defence
2001-06-06, Rudbecksalen, Rudbecklaboratoriet, Sjukhusvägen 10, Akademiska sjukhuset, 751 85 Uppsala, Uppsala, 09:15
Available from: 2001-05-16 Created: 2001-05-16 Last updated: 2018-01-13Bibliographically approved

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