Alteration of nuclear factor-kappaB (NF-kappaB) expression in bone marrow stromal cells treated with etoposide
| Autor: | B M, Hall, J E, Fortney, L F, Gibson |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Cell Nucleus
RNA Stability NF-kappa B Gene Expression Nuclear Proteins Vascular Cell Adhesion Molecule-1 Antineoplastic Agents Phytogenic DNA-Binding Proteins NF-KappaB Inhibitor alpha Bone Marrow Consensus Sequence Humans I-kappa B Proteins RNA Messenger Capsaicin Stromal Cells Cells Cultured Etoposide Subcellular Fractions |
| Zdroj: | Biochemical pharmacology. 61(10) |
| ISSN: | 0006-2952 |
| Popis: | Bone marrow stromal cells are an essential regulatory component in the hematopoietic microenvironment. Regulation of hematopoietic cell development is mediated, in part, through interaction of progenitor cells with stromal cell vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 expression has been shown to be driven primarily by binding of nuclear factor-kappaB (NF-kappaB) to two consensus binding sites in the promoter region. In this study, we show that down-regulation of VCAM-1 by the chemotherapeutic agent etoposide (VP-16) is associated with altered cellular localization of NF-kappaB. We demonstrated that VCAM-1 was diminished at the transcriptional level following treatment of stromal cells with VP-16, without alteration of VCAM-1 stability. Culture of bone marrow stromal cells in VP-16 resulted in reduced nuclear RelA (p65), a modest increase in nuclear NF-kappaB1 (p50), and reduced NF-kappaB binding to its DNA consensus sequence. Total levels of the NF-kappaB inhibitor Ikappa-Balpha were reduced during exposure to VP-16. Following removal of VP-16 from the culture, p65 and p50 nuclear profiles approximated those of untreated stromal cells, and VCAM-1 protein expression was restored. The current study indicates that NF-kappaB is a target molecule that is responsive to VP-16-induced damage in bone marrow stromal cells. As the primary transcription factor that promotes VCAM-1 expression, the observed changes in p65 and p50 cellular localization during treatment have a direct consequence for stromal cell function. The myriad of genes regulated by NF-kappaB, including both adhesion molecules and cytokines that contribute to stromal cell function, make chemotherapy-induced disruption of NF-kappaB biologically significant. Alterations in NF-kappaB activity may provide one measure by which the effects of aggressive treatment strategies on the bone marrow microenvironment can be evaluated. |
| Databáze: | OpenAIRE |
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