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Transmembrane interactions in lymphocytes: signaling alterations in lymphomas and myelomas tumor cells

English title Transmembrane interactions in lymphocytes: signaling alterations in lymphomas and myelomas tumor cells
Applicant Hoessli Daniel
Number 120368
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Cellular Biology, Cytology
Start/End 01.04.2008 - 30.09.2009
Approved amount 139'500.00
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Keywords (3)

Transmembrane signaling; lymphomas; myelomas

Lay Summary (English)

Lead
Lay summary
Human lymphomas and myelomas result from genetic and biochemical alterations occurring in B-lymphocytes during their differentiation and response to antigens. Those cancer cells exhibit a simplified organization of signaling (signalosome) in their cell membranes, consisting of a limited number of signaling proteins. Signalosomes are concentrated in specialized microdomains of the cell membrane called lipid rafts, where they appear to find optimal conditions for continued activity. Lipid rafts are enriched in sphingolipids that form compact segments of the plasma membrane (liquid-ordered state) and may allow the stable interaction of signalling proteins.Cancer cells in general tend to simplify the organization of their receptors to respond to signals of the environment. As a result, cancer cells finally rely on very few membrane-bound enzymes (tyrosine kinases) to initiate those responses and their signaling mechanisms tend to become autonomous. Cancer cells are said to become "addicted" to tyrosine kinases, a concept elaborated following the realization that cancer cells are easily killed by tyrosine kinase inhibitors. The “addicted” cancer cell activates preferentially the intracellular pathways supporting proliferation, but still contains active signalling pathways for apoptosis, albeit at low levels. Once tyrosine kinases are inhibited, the activity of proliferation pathways sharply decreases and falls below the level of activation of apoptosis pathways. Cells treated in this way tend to die by activation of their own apoptosis pathways.This project intends to investigate how lymphomas and myelomas assemble a signalosome to proliferate and resist programmed cell death. We have identified the tyrosine kinase Lyn and the adaptor proteins Cbp/PAG as the core of the lymphoma signalosome shall further investigate through which other signalling proteins this signalosome is linked to the proliferation and apoptosis pathways. We also intend to define how this signalosome may be perturbed and lead to the elimination of the cancer cell. Given that signalosomes assemble in lipid rafts, we shall look for ways to modify lipid rafts that result in signalosome inactivation.The goal of the project is to provide information on how lymphoma and myeloma cells could be exposed to compounds that modify their membrane organization and cause cell death by decreasing the activity of membrane-bound signalosomes.We intend to define how this signalosome may be perturbed and lead to the elimination of the cancer cell. Given that signalosomes are concentrated in specialized microdomains of the cell membrane called lipid rafts, ways to modify lipid rafts that result in signalosome inactivation will be also investigated.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
102158 Transmembrane interactions in lymphocytes: Sphingolipid micro- domains in lymphocyte signaling 01.10.2003 Project funding

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