PML/RARα plays a role for basal activity and retinoid-induced repression of the tissue factor promoter in acute promyelocytic leukemia cells

Taavo Tenno; Fredrik Öberg; Nigel Mackman; Kenneth Nilsson; Agneta Siegbahn

doi:10.1160/TH03-02-0087

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(05): 930-939
DOI: 10.1160/TH03-02-0087

Cellular Proteolysis and Oncology

Schattauer GmbH

PML/RARα plays a role for basal activity and retinoid-induced repression of the tissue factor promoter in acute promyelocytic leukemia cells

Taavo Tenno

¹Department of Medical Sciences, Laboratory for Coagulation Research, University Hospital, Uppsala, Sweden

²Department of Hematology and Oncology, University of Tartu, Tartu, Estonia

,

Fredrik Öberg

³Department of Genetics and Pathology, Rudbeck Laboratory, University Hospital, Uppsala, Sweden

,

Nigel Mackman

⁴Department of Immunology, The Scripps Research Institute, La Jolla, USA

,

Kenneth Nilsson

³Department of Genetics and Pathology, Rudbeck Laboratory, University Hospital, Uppsala, Sweden

,

Agneta Siegbahn

¹Department of Medical Sciences, Laboratory for Coagulation Research, University Hospital, Uppsala, Sweden

› Author Affiliations

Abstract

Summary

Constitutive expression of tissue factor (TF) by acute promyelocytic leukemia (APL) cells may contribute to thrombotic complications. In this study we examined the transcriptional mechanisms of all-transretinoic acid (ATRA)-induced down-regulation of TF in the APL cell line NB4, by analysis of stable clones expressing the luciferase gene under the control of 5’ flanking regions of the TF gene. We show that the TF promoter is constitutively active in NB4 cells, and that ATRA induces rapid suppression of the promoter. Basal activity and ATRA-induced suppression of TF promoter is determined by the proximal -383 to +121 bp of the promoter. Electrophoretic mobility shift assays demonstrate the binding of Fos/Jun complexes to two TF promoter AP-1 sites in this region. Both complexes were suppressed by ATRA treatment. The ectopic expression of the APL-specific PML/RARα oncoprotein in U-937 cells results in induction of TF mRNA and promoter activity. Interestingly, this PML/RARα-mediated increase in TF promoter activity is sensitive to ATRA treatment. These data indicate that TF expression in APL cells is exacerbated by the presence of the PML/RARα fusion protein, and implicates the loss of Fos/Jun binding to the TF promoter in ATRA-induced suppression of TF.

Keywords

Tissue factor - acute promyelocytic leukemia - retinoic acid - PML/RARα - AP-1

Full Text

References

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