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Multiple actions of lysophosphatidic acid on fibroblasts revealed by transcriptional profiling.

Stortelers C, Kerkhoven R, Moolenaar WH - BMC Genomics (2008)

Bottom Line: The subset of LPA-specific genes was enriched for those associated with cytoskeletal remodeling, in keeping with LPA's ability to regulate cell shape and motility.This study highlights the importance of LPA in programming fibroblasts not only to proliferate and migrate but also to produce many paracrine mediators of tissue remodeling, angiogenesis, inflammation and tumor progression.Furthermore, our results show that G protein-coupled receptors and receptor tyrosine kinases can signal independently to regulate broadly overlapping sets of genes in the same cell type.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cellular Biochemistry and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. c.stortelers@gmail.com

ABSTRACT

Background: Lysophosphatidic acid (LPA) is a lipid mediator that acts through specific G protein-coupled receptors to stimulate the proliferation, migration and survival of many cell types. LPA signaling has been implicated in development, wound healing and cancer. While LPA signaling pathways have been studied extensively, it remains unknown how LPA affects global gene expression in its target cells.

Results: We have examined the temporal program of global gene expression in quiescent mouse embryonic fibroblasts stimulated with LPA using 32 k oligonucleotide microarrays. In addition to genes involved in growth stimulation and cytoskeletal reorganization, LPA induced many genes that encode secreted factors, including chemokines, growth factors, cytokines, pro-angiogenic and pro-fibrotic factors, components of the plasminogen activator system and metalloproteases. Strikingly, epidermal growth factor induced a broadly overlapping expression pattern, but some 7% of the genes (105 out of 1508 transcripts) showed differential regulation by LPA. The subset of LPA-specific genes was enriched for those associated with cytoskeletal remodeling, in keeping with LPA's ability to regulate cell shape and motility.

Conclusion: This study highlights the importance of LPA in programming fibroblasts not only to proliferate and migrate but also to produce many paracrine mediators of tissue remodeling, angiogenesis, inflammation and tumor progression. Furthermore, our results show that G protein-coupled receptors and receptor tyrosine kinases can signal independently to regulate broadly overlapping sets of genes in the same cell type.

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Ingenuity pathway analysis of gene expression at two different LPA concentrations. Note relative enrichment of 'cell movement' genes at the lower LPA concentration.
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Figure 7: Ingenuity pathway analysis of gene expression at two different LPA concentrations. Note relative enrichment of 'cell movement' genes at the lower LPA concentration.

Mentions: The early cellular responses to LPA, such as cytoskeletal reorganization and migration, usually show their maximal induction in the submicromolar concentration range, while cell cycle progression requires 1–5 μM doses. We determined the dose-efficacy of LPA on gene transcription using three different concentrations (0.3, 1.0 and 5 μM) and analyzed expression profiles over time (0–4 hrs). The regulation of many LPA target genes was preserved at the lowest LPA dose tested (0.3 μM). About 65% of all target genes showed significant regulation by LPA at all three LPA doses (P-values < 0.01; although in many cases the ratios decreased below the threshold of 1.7-fold induction). Increasing the LPA concentration caused increasingly stronger gene expression, often with more prolonged kinetics, as visualized by heat map (Figure 5) and quantitated for selected genes by qPCR (Figure 6). It is of note that many of the genes encoding secreted factors (Il1rl1, Pai2, Ccl2, Ccl7, Cx3Cl1, Hbegf, Vegf) reached their maximal expression already at 0.3 μM LPA. "Ingenuity" pathway analysis indicated that the functional categories modulated by LPA were preserved at all three concentrations, with the notable exception that lowering the LPA dose to 0.3 μM led to a relative enrichment of genes associated with "cell movement" (Figure 7). This result is consistent with LPA's propensity to act as a motility factor and chemo-attractant rather than a growth factor in the lower concentration range.


Multiple actions of lysophosphatidic acid on fibroblasts revealed by transcriptional profiling.

Stortelers C, Kerkhoven R, Moolenaar WH - BMC Genomics (2008)

Ingenuity pathway analysis of gene expression at two different LPA concentrations. Note relative enrichment of 'cell movement' genes at the lower LPA concentration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2536681&req=5

Figure 7: Ingenuity pathway analysis of gene expression at two different LPA concentrations. Note relative enrichment of 'cell movement' genes at the lower LPA concentration.
Mentions: The early cellular responses to LPA, such as cytoskeletal reorganization and migration, usually show their maximal induction in the submicromolar concentration range, while cell cycle progression requires 1–5 μM doses. We determined the dose-efficacy of LPA on gene transcription using three different concentrations (0.3, 1.0 and 5 μM) and analyzed expression profiles over time (0–4 hrs). The regulation of many LPA target genes was preserved at the lowest LPA dose tested (0.3 μM). About 65% of all target genes showed significant regulation by LPA at all three LPA doses (P-values < 0.01; although in many cases the ratios decreased below the threshold of 1.7-fold induction). Increasing the LPA concentration caused increasingly stronger gene expression, often with more prolonged kinetics, as visualized by heat map (Figure 5) and quantitated for selected genes by qPCR (Figure 6). It is of note that many of the genes encoding secreted factors (Il1rl1, Pai2, Ccl2, Ccl7, Cx3Cl1, Hbegf, Vegf) reached their maximal expression already at 0.3 μM LPA. "Ingenuity" pathway analysis indicated that the functional categories modulated by LPA were preserved at all three concentrations, with the notable exception that lowering the LPA dose to 0.3 μM led to a relative enrichment of genes associated with "cell movement" (Figure 7). This result is consistent with LPA's propensity to act as a motility factor and chemo-attractant rather than a growth factor in the lower concentration range.

Bottom Line: The subset of LPA-specific genes was enriched for those associated with cytoskeletal remodeling, in keeping with LPA's ability to regulate cell shape and motility.This study highlights the importance of LPA in programming fibroblasts not only to proliferate and migrate but also to produce many paracrine mediators of tissue remodeling, angiogenesis, inflammation and tumor progression.Furthermore, our results show that G protein-coupled receptors and receptor tyrosine kinases can signal independently to regulate broadly overlapping sets of genes in the same cell type.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cellular Biochemistry and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. c.stortelers@gmail.com

ABSTRACT

Background: Lysophosphatidic acid (LPA) is a lipid mediator that acts through specific G protein-coupled receptors to stimulate the proliferation, migration and survival of many cell types. LPA signaling has been implicated in development, wound healing and cancer. While LPA signaling pathways have been studied extensively, it remains unknown how LPA affects global gene expression in its target cells.

Results: We have examined the temporal program of global gene expression in quiescent mouse embryonic fibroblasts stimulated with LPA using 32 k oligonucleotide microarrays. In addition to genes involved in growth stimulation and cytoskeletal reorganization, LPA induced many genes that encode secreted factors, including chemokines, growth factors, cytokines, pro-angiogenic and pro-fibrotic factors, components of the plasminogen activator system and metalloproteases. Strikingly, epidermal growth factor induced a broadly overlapping expression pattern, but some 7% of the genes (105 out of 1508 transcripts) showed differential regulation by LPA. The subset of LPA-specific genes was enriched for those associated with cytoskeletal remodeling, in keeping with LPA's ability to regulate cell shape and motility.

Conclusion: This study highlights the importance of LPA in programming fibroblasts not only to proliferate and migrate but also to produce many paracrine mediators of tissue remodeling, angiogenesis, inflammation and tumor progression. Furthermore, our results show that G protein-coupled receptors and receptor tyrosine kinases can signal independently to regulate broadly overlapping sets of genes in the same cell type.

Show MeSH
Related in: MedlinePlus