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Role of phosphoinositide-3-kinase in autocrine transformation by PDGF-BB.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
2001 In: Journal of Cellular Physiology, ISSN 0021-9541, Vol. 188, no 3, 369-382 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2001. Vol. 188, no 3, 369-382 p.
URN: urn:nbn:se:uu:diva-94027OAI: oai:DiVA.org:uu-94027DiVA: diva2:167715
Available from: 2006-02-10 Created: 2006-02-10Bibliographically approved
In thesis
1. Signal Transduction in Malignant Cells – Transformation, Activation and Differentiation
Open this publication in new window or tab >>Signal Transduction in Malignant Cells – Transformation, Activation and Differentiation
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

All aspects of cell life are regulated by signal transduction mechanisms. This thesis describes the regulatory roles of a few key signal transduction molecules involved in three major biological responses. The studied pathways include platelet derived growth factor (PDGF)-BB induced transformation of murine fibroblasts, interferon (IFN)-γ stimulated monocyte activation and all-trans retinoic acid (ATRA) induced myeloid differentiation.

We found that intact phosphoinositide 3OH-kinase (PI3K) activity is essential in the signaling pathway that leads to the morphological alterations and migration pattern characteristic of PDGF-BB transformed NIH/sis and NIH/COL1A1 fibroblasts. Furthermore, our data indicated that the small Rho-GTPase, Rac1 is the predominant mediator of these signals downstream of PI3K.

The study of the IFN-γ induced activation of monocytic U-937 cells showed that upregulation of the high affinity receptor for IgG (FcγRI) is dependent on the coordination of several regulatory events: the PKR-mediated serine 727 phosphorylation of Stat1, the expression of the hematopoietic lineage specific transcription factor PU.I, and the activation of the NFκB pathway.

ATRA-induced differentiation and cell cycle arrest are impaired in U-937 sublines expressing phosphorylation deficient Stat1 (Stat1Y701F and Stat1S727A). The findings in paper III indicated that the expression pattern of the myeloid specific transcription factors Stat2, ICSBP and c/EBPε was altered in the sublines and that intact Stat1 activation is critical for maintaining the balance of the transcriptional network during ATRA induced terminal differentiation.

Finally, ATRA-induced differentiation and growth arrest were blocked by treatment with the IKKα/β inhibitor BMS345541 or by ectopic expression of the NFκB super repressor IκBα (S32A/S36A). The fact that IκB(AA) sublines differentiated normally in response to vitamin D3, showed that NFκB inhibition specifically affected ATRA induced responses. Notably we suggest that the activity of the NFκB pathway may interfere with the differentiation process via a direct effect on the RAR/RXR mediated transcription.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 49 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 107
Molecular medicine, transformation, PDGF, PI3K, Rho-GTPase, U-937, FcγRI, macrophage, Stat1, PKR, NFκB, ATRA, differentiation, Molekylärmedicin
National Category
Medical Genetics
Research subject
urn:nbn:se:uu:diva-6346 (URN)91-554-6465-3 (ISBN)
Public defence
2006-03-10, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarsköldsväg 20, Uppsala, 09:15
Available from: 2006-02-10 Created: 2006-02-10 Last updated: 2013-09-04Bibliographically approved

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