Regulation of tissue factor expression in myeloid and monocytic leukaemia cells
Tissue factor (TF) is a transmembrane glycoprotein that initiates the blood coagulation cascade and is also involved in cell migration, tumour metastasis and angiogenesis. Pathologic expression of tissue factor by monocytes contributes to several thrombotic complications like acute coronary artery d...
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Uppsala universitet, Institutionen för medicinska vetenskaper
2001
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ndltd-UPSALLA1-oai-DiVA.org-uu-6182013-01-08T13:05:25ZRegulation of tissue factor expression in myeloid and monocytic leukaemia cellsengTenno, TaavoUppsala universitet, Institutionen för medicinska vetenskaperUppsala : Acta Universitatis Upsaliensis2001Medical sciencestissue factorblood coagulationmonocytescell differentiationretinoic acidvitamin D3acute promyelocytic leukaemiaMEDICIN OCH VÅRDMEDICINEMEDICINTissue factor (TF) is a transmembrane glycoprotein that initiates the blood coagulation cascade and is also involved in cell migration, tumour metastasis and angiogenesis. Pathologic expression of tissue factor by monocytes contributes to several thrombotic complications like acute coronary artery disease and disseminated intravascular coagulation. The aim of this thesis was to investigate the clinically important pathologic expression of TF in myelo-monocytic leukaemia cells and reveal the cellular signals leading to the suppression of TF expression. The studies in this thesis indicate that TF is a marker of immature myelo-monocytic cells. Markedly higher levels of TF were expressed in immature myelo-monocytic cell lines compared to mature monocyte-like cells. Induction of terminal differentiation in immature cells resulted in down-regulation of TF expression, irrespective of the specific phenotypes induced by retinoic acid (RA) or vitamin D3 in monoblastic U-937 cells. TF suppression was also found independent of differentiation pathways, i.e. monocytic or granulocytic. The nuclear receptor activation requirements for transcriptional suppression of TF by retinoic acid (RA) were shown to differ between acute promyelocytic leukaemia (APL) NB4 and U-937 cells. In NB4 cells the binding of the agonist to the RA receptor (RAR)α alone is needed for down-regulation of TF, whereas ligand binding to both RARαand retinoic X receptor was necessary for efficient suppression of TF expression in U-937 cells. To analyse the transcriptional regulation of TF, stable NB4 and U-937 clones expressing the luciferase gene under the control of various 5' flanking regions of the TF gene were selected. Different promoter regions were found to control the basal TF transcriptional activity. Analysis of protein binding to the 140 bp promoter region, responsible for basal TF activity in NB4 cells, revealed binding of RFX-1. RA suppressed the promoter activity in NB4, but not in U-937 cells. The ectopic expression of the APL fusion proteins PML/RARα or PLZF/RARα in U-937 reporter clones were shown to confer sensitivity to RA-induced suppression of TF promoter activity. These results provide a more detailed picture of TF regulation in leukaemic and haematopoietic cells and may have a bearing on new clinical treatment strategies in APL and other leukaemias. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-618urn:isbn:91-554-4966-2Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 ; 1011application/pdfinfo:eu-repo/semantics/openAccess |
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NDLTD |
language |
English |
format |
Doctoral Thesis |
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Medical sciences tissue factor blood coagulation monocytes cell differentiation retinoic acid vitamin D3 acute promyelocytic leukaemia MEDICIN OCH VÅRD MEDICINE MEDICIN |
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Medical sciences tissue factor blood coagulation monocytes cell differentiation retinoic acid vitamin D3 acute promyelocytic leukaemia MEDICIN OCH VÅRD MEDICINE MEDICIN Tenno, Taavo Regulation of tissue factor expression in myeloid and monocytic leukaemia cells |
description |
Tissue factor (TF) is a transmembrane glycoprotein that initiates the blood coagulation cascade and is also involved in cell migration, tumour metastasis and angiogenesis. Pathologic expression of tissue factor by monocytes contributes to several thrombotic complications like acute coronary artery disease and disseminated intravascular coagulation. The aim of this thesis was to investigate the clinically important pathologic expression of TF in myelo-monocytic leukaemia cells and reveal the cellular signals leading to the suppression of TF expression. The studies in this thesis indicate that TF is a marker of immature myelo-monocytic cells. Markedly higher levels of TF were expressed in immature myelo-monocytic cell lines compared to mature monocyte-like cells. Induction of terminal differentiation in immature cells resulted in down-regulation of TF expression, irrespective of the specific phenotypes induced by retinoic acid (RA) or vitamin D3 in monoblastic U-937 cells. TF suppression was also found independent of differentiation pathways, i.e. monocytic or granulocytic. The nuclear receptor activation requirements for transcriptional suppression of TF by retinoic acid (RA) were shown to differ between acute promyelocytic leukaemia (APL) NB4 and U-937 cells. In NB4 cells the binding of the agonist to the RA receptor (RAR)α alone is needed for down-regulation of TF, whereas ligand binding to both RARαand retinoic X receptor was necessary for efficient suppression of TF expression in U-937 cells. To analyse the transcriptional regulation of TF, stable NB4 and U-937 clones expressing the luciferase gene under the control of various 5' flanking regions of the TF gene were selected. Different promoter regions were found to control the basal TF transcriptional activity. Analysis of protein binding to the 140 bp promoter region, responsible for basal TF activity in NB4 cells, revealed binding of RFX-1. RA suppressed the promoter activity in NB4, but not in U-937 cells. The ectopic expression of the APL fusion proteins PML/RARα or PLZF/RARα in U-937 reporter clones were shown to confer sensitivity to RA-induced suppression of TF promoter activity. These results provide a more detailed picture of TF regulation in leukaemic and haematopoietic cells and may have a bearing on new clinical treatment strategies in APL and other leukaemias. |
author |
Tenno, Taavo |
author_facet |
Tenno, Taavo |
author_sort |
Tenno, Taavo |
title |
Regulation of tissue factor expression in myeloid and monocytic leukaemia cells |
title_short |
Regulation of tissue factor expression in myeloid and monocytic leukaemia cells |
title_full |
Regulation of tissue factor expression in myeloid and monocytic leukaemia cells |
title_fullStr |
Regulation of tissue factor expression in myeloid and monocytic leukaemia cells |
title_full_unstemmed |
Regulation of tissue factor expression in myeloid and monocytic leukaemia cells |
title_sort |
regulation of tissue factor expression in myeloid and monocytic leukaemia cells |
publisher |
Uppsala universitet, Institutionen för medicinska vetenskaper |
publishDate |
2001 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-618 http://nbn-resolving.de/urn:isbn:91-554-4966-2 |
work_keys_str_mv |
AT tennotaavo regulationoftissuefactorexpressioninmyeloidandmonocyticleukaemiacells |
_version_ |
1716508544757399552 |