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Differential RelA- and RelB-dependent gene transcription in LTbetaR-stimulated mouse embryonic fibroblasts.

ABSTRACT: BACKGROUND: Lymphotoxin signaling via the lymphotoxin-beta receptor (LTbetaR) has been implicated in biological processes ranging from development of secondary lymphoid organs, maintenance of spleen architecture, host defense against pathogens, autoimmunity, and lipid homeostasis. The major transcription factor that is activated by LTbetaR crosslinking is NF-kappaB. Two signaling pathways have been described, the classical inhibitor of NF-kappaB alpha (IkappaBalpha)-regulated and the alternative p100-regulated pathway that result in the activation of p50-RelA and p52-RelB NF-kappaB heterodimers, respectively. RESULTS: Using microarray analysis, we investigated the transcriptional response downstream of the LTbetaR in mouse embryonic fibroblasts (MEFs) and its regulation by the RelA and RelB subunits of NF-kappaB. We describe novel LTbetaR-responsive genes that were regulated by RelA and/or RelB. The majority of LTbetaR-regulated genes required the presence of both RelA and RelB, revealing significant crosstalk between the two NF-kappaB activation pathways. Gene Ontology (GO) analysis confirmed that LTbetaR-NF-kappaB target genes are predominantly involved in the regulation of immune responses. However, other biological processes, such as apoptosis/cell death, cell cycle, angiogenesis, and taxis were also regulated by LTbetaR signaling. Moreover, LTbetaR activation inhibited expression of a key adipogenic transcription factor, peroxisome proliferator activated receptor-gamma (pparg), suggesting that LTbetaR signaling may interfere with adipogenic differentiation. CONCLUSION: Microarray analysis of LTbetaR-stimulated fibroblasts provided comprehensive insight into the transcriptional response of LTbetaR signaling and its regulation by the NF-kappaB family members RelA and RelB.

SUBMITTER: Lovas A

PROVIDER: S-EPMC2637282 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Differential RelA- and RelB-dependent gene transcription in LTbetaR-stimulated mouse embryonic fibroblasts.

Lovas Agnes A Radke Dörte D Albrecht Daniela D Yilmaz Z Buket ZB Möller Ulrich U Habenicht Andreas J R AJ Weih Falk F

BMC genomics 20081216

<h4>Background</h4>Lymphotoxin signaling via the lymphotoxin-beta receptor (LTbetaR) has been implicated in biological processes ranging from development of secondary lymphoid organs, maintenance of spleen architecture, host defense against pathogens, autoimmunity, and lipid homeostasis. The major transcription factor that is activated by LTbetaR crosslinking is NF-kappaB. Two signaling pathways have been described, the classical inhibitor of NF-kappaB alpha (IkappaBalpha)-regulated and the alte ...[more]

PMID: 19087315

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Project description:Vitamin C has been shown to delay the cellular senescence and was considered a candidate for chemoprevention and cancer therapy. To understand the reported contrasting roles of vitamin C: growth-promoting in the primary cells and growth-inhibiting in cancer cells, primary mouse embryonic fibroblasts (MEF) and their isogenic spontaneously immortalized fibroblasts with unlimited cell division potential were used as the model pair. We used microarray gene expression profiling to show that the immortalized MEF possess human cancer gene expression fingerprints including a pattern of up-regulation of inflammatory response-related genes. Using the MEF model, we found that a physiological treatment level of vitamin C (10(-5) M), but not other unrelated antioxidants, enhanced cell growth. The growth-promoting effect was associated with a pattern of enhanced expression of cell cycle- and cell division-related genes in both primary and immortalized cells. In the immortalized MEF, physiological treatment levels of vitamin C also enhanced the expression of immortalization-associated genes including a down-regulation of genes in the extracellular matrix functional category. In contrast, confocal immunofluorescence imaging of the primary MEF suggested an increase in collagen IV protein upon vitamin C treatment. Similar to the cancer cells, the growth-inhibitory effect of the redox-active form of vitamin C was preferentially observed in immortalized MEF. All effects of vitamin C required its intracellular presence since the transporter-deficient SVCT2-/- MEF did not respond to vitamin C. SVCT2-/- MEF divided and became immortalized readily indicating little dependence on vitamin C for the cell division. Immortalized SVCT2-/- MEF required higher concentration of vitamin C for the growth inhibition compared to the immortalized wildtype MEF suggesting an intracellular vitamin C toxicity. The relevance of our observation in aging and human cancer prevention was discussed.

Dataset Information

Differential RelA- and RelB-dependent gene transcription in LTbetaR-stimulated mouse embryonic fibroblasts.

Publications

Differential RelA- and RelB-dependent gene transcription in LTbetaR-stimulated mouse embryonic fibroblasts.

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