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

Authors

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

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

References
1 Edgington TS, Mackman N, Brand K. et al The structural biology of expression and function of tissue factor. Thromb Haemost 1991; 66: 67-79.
2 Falanga A, Iacoviello L, Evangelista V. et al Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-retinoic acid. Blood 1995; 86: 1072-81.
3 Tenno T, Öberg F, Nilsson K. et al Induction of differentiation in U-937 and NB4 cells is associated with inhibition of tissue factor production. Eur J Haematol 1999; 63: 112-9.
4 Conese M, Montemurro P, Fumarulo R. et al Inhibitory effect of retinoids on the generation of procoagulant activity by blood mononuclear phagocytes. Thromb Haemost 1991; 66: 662-5.
5 Ott I, Fischer EG, Miyagi Y. et al A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J Cell Biol 1998; 140: 1241-53.
6 Siegbahn A, Johnell M, Rorsman C. et al Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis. Blood 2000; 96: 3452-8.
7 Bromberg ME, Konigsberg WH, Madison JF. et al Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci U S A 1995; 92: 8205-9.
8 Carmeliet P, Mackman N, Moons L. et al Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-5.
9 Minucci S, Pelicci PG. Retinoid receptors in health and disease: co-regulators and the chromatin connection. Semin Cell Dev Biol 1999; 10: 215-25.
10 Melnick A, Licht JD. Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93: 3167-215.
11 Lin RJ, Egan DA, Evans RM. Molecular genetics of acute promyelocytic leukemia. Trends Genet 1999; 15: 179-84.
12 Mackman N. Regulation of the tissue factor gene. Thromb Haemost 1997; 78: 747-54.
13 Mackman N, Brand K, Edgington TS. Lipopolysaccharide-mediated transcriptional activation of the human tissue factor gene in THP-1 monocytic cells requires both activator protein 1 and nuclear factor κB binding sites. J Exp Med 1991; 174: 1517-26.
14 Oeth PA, Parry GC, Kunsch C. et al Lipopolysaccharide induction of tissue factor gene expression in monocytic cells is mediated by binding of c-Rel/p65 heterodimers to a κB-like site. Mol Cell Biol 1994; 14: 3772-81.
15 Oeth PA, Yao J, Fan ST. et al Retinoic acid selectively inhibits lipopolysaccharide induction of tissue factor gene expression in human monocytes. Blood 1998; 91: 2857-65.
16 Koyama T, Hirosawa S, Kawamata N. et al All-trans retinoic acid upregulates thrombomodulin and downregulates tissue-factor expression in acute promyelocytic leukemia cells: distinct expression of thrombomodulin and tissue factor in human leukemic cells. Blood 1994; 84: 3001-9.
17 Tenno T, Botling J, Öberg F. et al The role of RAR and RXR activation in retinoid-induced tissue factor suppression. Leukemia 2000; 14: 1105-11.
18 Lanotte M, Martin-Thouvenin V, Najman S. et al NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3). Blood 1991; 77: 1080-6.
19 SundstrÖm C, Nilsson K. Establishment and characterization of a human histocytic lymphoma cell line (U-937). Int J Cancer 1976; 17: 565-77.
20 Grignani F, Ferrucci PF, Testa U. et al The acute promyelocytic leukemia-specific PMLRARα fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 1993; 74: 423-31.
21 Boehm MF, McClurg MR, Pathirana C. et al Synthesis of high specific activity [3H]-9-cisretinoic acid and its application for identifying retinoids with unusual binding properties. J Med Chem 1994; 37: 408-14.
22 Bollag W, Isnardi L, Jablonska S. et al Links between pharmacological properties of retinoids and nuclear retinoid receptors. Int J Cancer 1997; 70: 470-2.
23 Apfel C, Bauer F, Crettaz M. et al A retinoic acid receptor α antagonist selectively counteracts retinoic acid effects. Proc Natl Acad Sci U S A 1992; 89: 7129-33.
24 Mackman N, Fowler BJ, Edgington TS. et al Functional analysis of human tissue factor promoter and induction by serum. Proc Natl Acad Sci U S A 1990; 87: 2254-8.
25 Parry GC, Mackman N. Transcriptional regulation of tissue factor expression in human endothelial cells. Arterioscler Thromb Vasc Biol 1995; 15: 612-21.
26 Dimberg A, Nilsson K, Öberg F. Phosphorylation-deficient Stat1 inhibits retinoic acid-induced differentiation and cell cycle arrest in U-937 monoblasts. Blood 2000; 96: 2870-8.
27 Andrews NC, Faller DV. A rapid micro-preparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res 1991; 19: 2499
28 Oeth PA, Parry GC, Mackman N. Regulation of the tissue factor gene in human monocytic cells. Role of AP-1, NF-κB/Rel, and Sp1 proteins in uninduced and lipopolysaccharide-induced expression. Arterioscler Thromb Vasc Biol 1997; 17: 365-74.
29 Raelson JV, Nervi C, Rosenauer A. et al The PML/RARα oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood 1996; 88: 2826-32.
30 Nervi C, Ferrara FF, Fanelli M. et al Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARα fusion protein. Blood 1998; 92: 2244-51.
31 Warrell Jr. RP, de The H, Wang ZY. et al Acute promyelocytic leukemia. N Engl J Med 1993; 329: 177-89.
32 Thompson JF, Hayes LS, Lloyd DB. Modulation of firefly luciferase stability and impact on studies of gene regulation. Gene 1991; 103: 171-7.
33 Grignani F, Valtieri M, Gabbianelli M. et al PML/RARα fusion protein expression in normal human hematopoietic progenitors dictates myeloid commitment and the promyelocytic phenotype. Blood 2000; 96: 1531-7.
34 Weis K, Rambaud S, Lavau C. et al Retinoic acid regulates aberrant nuclear localization of PML-RARα in acute promyelocytic leukemia cells. Cell 1994; 76: 345-56.
35 Alcalay M, Tomassoni L, Colombo E. et al The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein. Mol Cell Biol 1998; 18: 1084-93.
36 LaMorte VJ, Dyck JA, Ochs RL. et al Localization of nascent RNA and CREB binding protein with the PML-containing nuclear body. Proc Natl Acad Sci U S A 1998; 95: 4991-6.
37 Liu SL, Rand A, Kelm Jr. RJ, Getz MJ. The retinoblastoma gene family members pRB and p107 coactivate the AP-1-dependent mouse tissue factor promoter in fibroblasts. Oncogene 2000; 19: 3352-62.
38 Parry GC, Mackman N. Role of cyclic AMP response element-binding protein in cyclic AMP inhibition of NF-κB-mediated transcription. J Immunol 1997; 159: 5450-6.
39 Ollivier V, Parry GCN, Cobb RR. et al Elevated cyclic AMP inhibits NF-κB-mediated transcription in human monocytic cells and endothelial cells. J Biol Chem 1996; 271: 20828-35.
40 Lee DU, Agarwal S, Rao A. Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. Immunity 2002; 16: 649-60.
41 Takai D, Jones PA. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A 2002; 99: 3740-5.
42 Yoshida H, Kitamura K, Tanaka K. et al Accelerated degradation of PML-retinoic acid receptor α (PML-RARα) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway. Cancer Res 1996; 56: 2945-8.
43 Chambon P. Adecade of molecular biology of retinoic acid receptors. FASEB J 1996; 10: 940-54.
44 Groupp ER, Donovan Peluso M. Lipopolysaccharide induction of THP-1 cells activates binding of c-Jun, Ets, and Egr-1 to the tissue factor promoter. J Biol Chem 1996; 271: 12423-30.
45 Vallian S, Gaken JA, Gingold EB. et al Modulation of Fos-mediated AP-1 transcription by the promyelocytic leukemia protein. Oncogene 1998; 16: 2843-53.
46 Schüle R, Rangarajan P, Yang N. et al Retinoic acid is a negative regulator of AP-1-responsive genes. Proc Natl Acad Sci U S A 1991; 88: 6092-6.
47 Zhou XF, Shen XQ, Shemshedini L. Ligand-activated retinoic acid receptor inhibits AP-1 transactivation by disrupting c-Jun/c-Fos dim-erization. Mol Endocrinol 1999; 13: 276-85.