Calcium-dependent upregulation of E4BP4 expression correlates with glucocorticoid-evoked apoptosis of human leukemic CEM cells

Priceman, Saul J.; Kirzner, Jonathan; Nary, Laura J; Morris, Devin; Shankar, Deepa B.; Sakamoto, Kathleen M.; Medh, Rheem D.

doi:10.1016/j.bbrc.2006.03.169

Cited by 16 publications

(21 citation statements)

References 36 publications

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“…E4BP4 was inhibited by dexamethasone because its 2 -DDCt value was the lowest (0.185). These results corroborated the PTHrP specificity in inducing E4BP4, whereas its suppression by dexamethasone was contrary to previous data in T lymphoblasts (17). The defective E4BP4 induction by dickkopf1 (2 -DDCt = 0.890) is in line with the independence of this osteoblast inhibitor from the PTH-1-R pathway.…”

Section: Resultssupporting

confidence: 78%

“…E4BP4 is also inducible by IL-3 and glucocorticoids in B and T cells, respectively (16,17). With the purpose of exploring their effect on osteoblasts, we stimulated them with IL-3 and dexamethasone and measured the expression of E4BP4 and morphogenetic factors.…”

Section: Discussionmentioning

confidence: 99%

“…E4BP4, a repressor gene induced in osteoblasts through the type 1 parathyroid hormone receptor (PTH-1-R; ref. 15), by IL-3 in murine pro-B cells (16) and by glucocorticoids in human T lymphoblasts (17), was overexpressed. Hyperactivity of E4BP4 in myeloma-conditioned osteoblasts definitely inhibited the cyclooxygenase-2 (COX-2) pathway that regulates the expression of both Runx2 and Osterix (18).…”

mentioning

confidence: 98%

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Negative Regulation of the Osteoblast Function in Multiple Myeloma through the Repressor Gene E4BP4 Activated by Malignant Plasma Cells

Silvestris

Cafforio

Matteo

et al. 2008

Clinical Cancer Research

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Purpose: To explore the pathogenetic mechanisms that suppress the osteoblast function in multiple myeloma because osteogenesis results in defective new bone formation and repair. Experimental Design: Microarray gene analysis revealed the overexpression of E4BP4, a transcriptional repressor gene, in normal osteoblasts cocultured with myeloma cells that were releasing the parathyroid hormone-related protein (PTHrP). Thus, the effect of E4BP4 was assessed in PTHrP-stimulated osteoblasts by measuring the RNA levels of both Runx2 and Osterix as major osteoblast transcriptional activators. Because E4BP4 is a negative regulator of the cyclooxygenase-2 (COX-2) pathway that drives the expression of both Runx2 and Osterix, these factors were investigated after prostaglandin E 2 treatment to overcome the COX-2 defect as well as in E4BP4-silenced osteoblasts. Finally, E4BP4, PTHrP, Osterix, and osteocalcin levels were measured in vivo in patients with bone disease together with the E4BP4 protein in bone biopsies. Results: E4BP4 was specifically induced by PTHrP and inhibited both Runx2 and Osterix, whereas E4BP4-silenced osteoblasts expressed functional levels of both factors.The prostaglandin E 2 treatment of E4BP4-up-regulated osteoblasts promptly restored Runx2 and Osterix activities, suggesting that integrity of COX-2 pathway is essential for their transcription. Down-regulation of Osterix by E4BP4 was confirmed in vivo by its inverse levels in osteoblasts from myeloma patients with increased serum PTHrP, whose bone biopsies expressed the E4BP4 protein.Conclusions: Our data support the role of E4BP4 as osteoblast transcriptional repressor in inhibiting both Runx2 and Osterix in myeloma bone disease and correlate its effect with the increased PTHrP activity.Myeloma bone disease (MBD) is the hallmark of multiple myeloma. It is primarily associated with hyperactive osteoclastogenesis promoted by malignant plasma cells and the bone destruction is not accompanied by compensatory remodeling (1). Minimal bone formation occurs early within the initial bone erosions (2), whereas osteoblast activity is suppressed as the disease progresses and is reflected by low serum levels of osteogenic markers as osteocalcin, type I collagen, alkaline phosphatase, and osteoprotegerin (3). Different mechanisms concurrently lead to osteoblast suppression. The canonical Wnt signaling pathway, which regulates pre-osteoblast differentiation by mesenchymal stem cells, is deranged by inhibitors produced by myeloma cells. They mainly include dickkopf1, whose RNA levels correlate with both serum protein and skeletal involvement (4), and the soluble Frizzled related protein-2 (5). Serum levels of other osteoblast-inhibiting factors, as noggin, gremlin, interleukin (IL)-3, IL-7, IL-11, and insulin growth factor binding protein 4, are also enhanced in MBD (6, 7).Osteogenic differentiation from mesenchymal cells is critically regulated by Runx2/Cbfa1 (8), a transcription factor that, through the downstream inducer Osterix/Sp7 (9), promotes the exp...

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

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Negative Regulation of the Osteoblast Function in Multiple Myeloma through the Repressor Gene E4BP4 Activated by Malignant Plasma Cells

Silvestris

Cafforio

Matteo

et al. 2008

Clinical Cancer Research

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“…The glucocorticoid receptor (GR) is normally regulated by a negative feedback mechanism upon activation; the GR mRNA and protein are down-regulated after GC addition 3 . However, in certain GC treated murine leukemic T cell lines, GR activation is not attenuated leading to glucocorticoid induced cell death 3,72,73 . The Nfil3 gene is induced under these conditions and is thought to be part of the mechanism that activates apoptosis.…”

Section: Nfil3 Influences Cellular Survivalmentioning

confidence: 98%

New Frontiers for the NFIL3 bZIP Transcription Factor in Cancer, Metabolism and Beyond

Keniry¹,

Dearth²,

Persans³

et al. 2014

Discoveries

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The bZIP transcription factor NFIL3 (Nuclear factor Interleukin 3 regulated, also known as E4 binding protein 4, E4BP4) regulates diverse biological processes from circadian rhythm to cellular viability. Recently, a host of novel roles have been identified for NFIL3 in immunological signal transduction, cancer, aging and metabolism. Elucidating the signaling pathways that are impacted by NFIL3 and the regulatory mechanisms that it targets, inhibits or activates will be critical for developing a clearer picture of its physiological roles in disease and normal processes. This review will discuss the recent advances and emerging issues regarding NFIL3-mediated transcriptional regulation of CEBPβ and FOXO1 activated genes and signal transduction.

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“…We have established a crucial relationship between GC-dependent upregulation of E4BP4 and sensitivity to GC-evoked apoptosis in the human leukemic CEM cell culture model [5]. E4BP4 (or NFIL3) is a bZIP transcription factor with a role in anti-inflammatory response, circadian oscillation, apoptosis regulation, and immune cell development [6- 8].…”

Section: Introductionmentioning

confidence: 99%

Correlation of glucocorticoid-mediated E4BP4 upregulation with altered expression of pro- and anti-apoptotic genes in CEM human lymphoblastic leukemia cells

Beach

Nary

Hovanessian

et al. 2014

Biochemical and Biophysical Research Communications

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In C.elegans, motoneuron apoptosis is regulated via a ces-2 – ces-1 – egl-1 pathway. We tested whether human CEM lymphoblastic leukemia cells undergo apoptosis via an analogous pathway. We have previously shown that E4BP4, a ces-2 ortholog, mediates glucocorticoid (GC)-dependent upregulation of BIM, an egl-1 ortholog, in GC-sensitive CEM C7-14 cells and in CEM C1-15 mE#3 cells, which are sensitized to GCs by ectopic expression of E4BP4. In the present study, we demonstrate that the human ces-1 orthologs, SLUG and SNAIL, are not significantly repressed in correlation with E4BP4 expression. Expression of E4BP4 homologs, the PAR family genes, especially HLF, encoding a known anti-apoptotic factor, was inverse to that of E4BP4 and BIM. Expression of pro- and anti-apoptotic genes in CEM cells was analyzed via an apoptosis PCR Array. We identified BIRC3 and BIM as genes whose expression paralleled that of E4BP4, while FASLG, TRAF4, BCL2A1, BCL2L1, BCL2L2 and CD40LG as genes whose expression was opposite to that of E4BP4.

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Calcium-dependent upregulation of E4BP4 expression correlates with glucocorticoid-evoked apoptosis of human leukemic CEM cells

Cited by 16 publications

References 36 publications

Negative Regulation of the Osteoblast Function in Multiple Myeloma through the Repressor Gene E4BP4 Activated by Malignant Plasma Cells

Negative Regulation of the Osteoblast Function in Multiple Myeloma through the Repressor Gene E4BP4 Activated by Malignant Plasma Cells

New Frontiers for the NFIL3 bZIP Transcription Factor in Cancer, Metabolism and Beyond

Correlation of glucocorticoid-mediated E4BP4 upregulation with altered expression of pro- and anti-apoptotic genes in CEM human lymphoblastic leukemia cells

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