The expression of immediate early gene X-1 (IEX-1) is differentially induced by retinoic acids in NB4 and KG1 cells: possible implication in the distinct phenotype of retinoic acid-responsive and -resistant leukemic cells

Abstract

In a cell-type- and stimulus-dependent fashion, the early response gene immediate early gene X-1 (IEX-1) is involved in growth control and modulation of apoptosis. The present study demonstrates that, in the two acute promyelocytic leukemia (APL) cell lines NB4 and KG1, exhibiting distinct responsiveness to retinoic acids (RAs), IEX-1 expression is rapidly (30-60 min) induced by all-trans- or cis-RA and independently of other signal transduction mediators, such as TNFalpha, NF-kappaB or MAP kinases. In NB4 cells (expressing PML-RARalpha), this increase is transient and completely reversible, along with a cell cycle arrest, ongoing differentiation and lower sensitivity to anti-cancer-drug-induced apoptosis. In contrast, the RA-induced IEX-1 expression in KG1 cells (expressing PLZF-RARalpha) persists over days, along with continued cell cycle progression and increased apoptotic sensitivity. Furthermore, two functional RA-response elements in the IEX-1 promoter were identified by gel shift and luciferase reporter gene assays. IEX-1 might be a rather unique transcriptional target of the two X-RARalpha fusion receptors exhibiting distinct responsiveness to RAs. Following a different time course of direct transcriptional induction by PML-RARalpha and PLZF-RARalpha in NB4 and KG1 cells, respectively, IEX-1 expression may be involved in the modified actions of these receptors and the distinct phenotypes of APL cells.

Differential gene expression of bone marrow-derived CD34+ cells is associated with survival of patients suffering from myelodysplastic syndrome

“…Therefore, IEX-1 as a potentially new mediator of apoptosis may represent an important insight into the molecular pathology of MDS. Retinoic acids and hydroxytamoxifen have been shown to induce IEX-1 expression in leukemic and breast cancer cells, respectively [58,59]. It remains to be seen if these or other agents are capable of efficient IEX-1 induction in MDS, and whether its induction may translate into inhibition of apoptosis, and ultimately improve blood cell counts of patients with MDS.…”

Immediate Early Gene X1 (IEX-1) Is Organized in Subnuclear Structures and Partially Co-localizes with Promyelocytic Leukemia Protein in HeLa Cells

“…IEX-1, as well as its rodent homologues PRG1 and gly96 (10,11), is a short lived protein consisting of 156 amino acids and shares no significant sequence similarities with any other known protein. The IEX-1 promoter is controlled by a large number of regulated transcription factors, including NF-B (6,8,12), AP1 (10,12), AP2 (10,12), VD3R (13), RAR (14), Sp1 (6,15), c-Myc (16), and p53 (6,8,15,16).…”

Immediate early gene X-1 interacts with proteins that modulate apoptosis

“…IEX-1 has been shown to be induced in cardiomyocytes and vascular smooth muscle cells by mechanical stretch, and overexpression of IEX-1 in vascular smooth muscle cells protects against stretch-induced hypertrophy [9,15] IEX-1 is regulated by a variety of factors. IEX-1 expression is increased by serum, X-, and UV-irradiation, growth factors such as epidermal growth factor, inflammatory stimuli such as lipopolysaccharide and ceramide, retinoids such as all-trans-retinoic acid or cis-retinoic acid, and by over-expression of Sp1 in cells [1][2][3]6,10,11,20,[24][25][26][27][28][29][30][31]. The gene is repressed by steroid hormones such as 1α, 25-dihydroxyvitamin D 3 and by over-expression of p53 [3,4,30,32].…”