The β2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms

Pullar, Christine E.; Isseroff, Roslyn Rivkah

doi:10.1242/jcs.02772

Cited by 78 publications

(65 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As demonstrated in several studies, the most common signaling pathways downstream ß2-AR in tumor cells are the cAMP/PKA, the MAPK/ERK1/2 and the PI3K/AKT signaling pathways (2,(17)(18)(19). Clinical studies demonstrate that the high expression and activity of ERK1/2 and PI3K/ AKT in HCC cells is associated with rapid tumor progression (20,21), whereas, the majority of studies on cAMP/PKA show that it is associated with the growth inhibition of HCC cells (22).…”

Section: Discussionmentioning

confidence: 96%

“…4A and B). The ß2-AR signaling was confirmed using ICI 118551, the specificity of the phosphorylation of ERK1/2 was confirmed using U0126, and the possible involvement of EGFR was ruled out using PD153035 (17)(18)(19). ISO-induced phosphorylation of ERK1/2 was effectively inhibited either by ICI 118551 (5 μM) or U0126 (10 μM), but not by PD153035 (25 μM).…”

Section: Iso Activates Mapk/erk1/2 By a ß2-ar-mediated And Egfr-indepmentioning

confidence: 90%

“…It has been demonstrated that the most frequently associated signaling pathways that downstream ß2-AR (G-protein-coupled receptor) are the adenyl cyclase/cyclic adenosine monophospatedependent protein kinase (cAMP/PKA), mitogen activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) and phosphatidylinositol-3-kinase/ AKT or protein kinase B (PI3K/AKT) signaling pathways (2,(17)(18)(19). We used the selective ß2-AR antagonist ICI 118551 to confirm the ß2-AR signaling, and the PKA inhibitor H-89, the MEK-specific inhibitor U0126, the PI3K inhibitor LY294002 and the specific EGFR tyrosine kinase inhibitor PD153035 to rule out the possible involvement of these signaling pathways in mediating the effect of ISO.…”

Section: ß2-ar-mediated Activation Of Both Mapk/erk1/2-dependent and mentioning

confidence: 99%

See 2 more Smart Citations

The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells

Yuan

Li²,

Li³

et al. 2009

Oncol Rep

View full text Add to dashboard Cite

Abstract.Increasing data indicate that stress hormones and their corresponding receptors play an important role in the carcinogenesis and progression of hepatocellular carcinoma (HCC). However, there is presently no study investigating the influence of stress hormones in correlation with ß2-AR on human HCC cells. We examined the expression of ·1-and ß-ARs in human HCC cell line HepG2 and MHCC97H cells in comparison with that in human normal hepatic cell line HL-7702 cells (L-02), and the influence of isoproterenol (ISO) on the growth of these HCC cells using blocking agents in correlation with ß2-AR and its downstream signaling pathways. We found that ·1-AR was down-regulated and ß2-AR was up-regulated in HepG2 and MHCC97H cells. ISO dosedependently promoted the growth of both HepG2 and MHCC97H cells. ISO-induced growth and survival of HCC cells were effectively attenuated by ICI 118551, U0126 and PD153035, but not by H-89 or LY294002. ISO transiently activated MAPK/ERK1/2 in tumor cells which could be blocked either by ICI 118551 or U0126, but not by H-89, LY294002, or PD153035. These findings indicate that ISO mimicking a mitogen promoted the growth of HepG2 and MHCC97H cells via ß2-AR-mediated activation of both MAPK/ERK1/2 dependent and independent signaling pathways, and ISO activated MAPK/ERK1/2 by an EGFRindependent mechanism.

show abstract

Section: Discussionmentioning

confidence: 96%

Section: Iso Activates Mapk/erk1/2 By a ß2-ar-mediated And Egfr-indepmentioning

confidence: 90%

Section: ß2-ar-mediated Activation Of Both Mapk/erk1/2-dependent and mentioning

confidence: 99%

See 1 more Smart Citation

The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells

Yuan

Li²,

Li³

et al. 2009

Oncol Rep

View full text Add to dashboard Cite

show abstract

“…Growing evidence suggests that EGFR is a key functional regulator of keratinocyte responses to a vast array of extracellular stimuli including specific EGFR ligands, ligands for other cell surface receptors such as G-protein-coupled and cytokine receptors, and a number of nonligand agents such as H2O2, UV, heat, radiation, and some chemotherapeutics (8,24,25,30). Disparate mechanisms of EGFR activation in skin cells under physiological and pathological conditions suggest that it could mediate numerous cellular functions, for example, changes of cell shape, proliferation, migration, adhesion, and inflammatory responses during wound healing (28,30,34,45). The experimental data demonstrate that the EGFR system plays a relevant role in the epidermal cell reaction to wounding, first by mounting a robust, but transient inflammation (7,26,27,30).…”

Section: Discussionmentioning

confidence: 99%

Plant Polyphenols Regulate Chemokine Expression and Tissue Repair in Human Keratinocytes Through Interaction with Cytoplasmic and Nuclear Components of Epidermal Growth Factor Receptor System

Pastore

Lulli

Fidanza

et al. 2012

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Aims: To evaluate mechanisms underlying modulation of inflammatory chemokines in primary human keratinocytes (normal human epidermal keratinocytes) and repair-related processes in wound models by plant polyphenols (PPs) with antioxidant and superoxide scavenging properties (verbascoside [Vb], resveratrol [Rv], polydatin [Pd], quercetin [Qr], and rutin). Results: Epidermal growth factor receptor (EGFR)-controlled chemokines CXCL8/interleukin 8 (IL-8), CCL2/monocyte chemotactic protein-1 (MCP-1), and CXCL10/interferon gamma-produced protein of 10 kDa (IP-10) were modulated by transforming growth factor alpha (TGF-a) and by the tumor necrosis factor alpha/interferon gamma combination (T/I). EGFR phosphorylation, nuclear translocation, and downstream cytoplasmic signaling pathways (extracellular regulation kinase [ERK]1/2, p38, STAT3, and PI-3K) were studied. All PPs did not affect TGF-a-induced STAT3 phosphorylation, whereas they suppressed T/I-activated NFkappaB and constitutive and T/I-induced but not TGF-a-induced ERK1/2 phosphorylation. Vb and Qr suppressed total EGFR phosphorylation, but they synergized with TGF-a to enhance nuclear accumulation of phosphorylated EGFR. Vb strongly inhibited TGF-a-induced p38 phosphorylation and T/I-induced NFkappaB and activator protein-1 (AP-1) binding to DNA. Vb was an effective inhibitor of T/I-stimulated chemokine synthesis, and it accelerated scratch wound healing in vitro. Anti-inflammatory and wound healing activities of Vb were confirmed in vivo in the full-thickness excision wound. Although Pd and Rv did not affect EGFR activation/translocation, they and Qr synergized with TGF-a and T/I in the induction of IL-8 transcription/synthesis while opposing enhanced MCP-1 and IP-10 transcription/synthesis connected with pharmacologically impaired EGFR functioning. Innovation: PPs perturb the EGFR system in human keratinocytes, and this effect may be implicated in the regulation of inflammatory and repair-related processes in the skin. Conclusion: Anti-inflammatory and wound healing effects of PPs depend on their interaction with EGFR-controlled cytoplasmic and nuclear pathways rather than on their direct redox properties. Antioxid. Redox Signal. 16, 314-328.

show abstract

“…Apart from direct activation by its protein ligands, EGFR can be activated by heterogeneous ligands or EGFR ligand-independent mechanisms including a variety of G-proteincoupled receptor ligands and by proinflammatory cytokines binding their specific receptors and integrins [15][16][17][18] .…”

Section: Discussionmentioning

confidence: 99%

Treatment of Cultured Sebocytes with an EGFR Inhibitor Does Not Lead to Significant Upregulation of Inflammatory Biomarkers

et al. 2011

View full text Add to dashboard Cite

Background: Epidermal growth factor receptor (EGFR) inhibitors are being used to treat malignancies originating from epithelia. Unfortunately, blocking the EGFR pathway leads to various side effects, most frequently acneiform eruptions. Objective: To probe the mechanism underlying this side effect, we investigated the effect of EGFR inhibitors on cultured sebocytes. Methods: To examine the effects of an EGFR inhibitor (cetuximab, Erbitux Ⓡ 10 ng/ml) and the effects of EGFR ligands, such as epidermal growth factor (EGF, 10 ng/ml) and transforming growth factor-α (TGF-α, 5 ng/ml), on the production of inflammatory cytokines in cultured sebocytes, we used reverse transcriptase-polymerase chain reaction, immunocytofluorescence and Western blots. Outcomes included the expression of interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α), peroxisome proliferator-activated receptor-γ (PPAR-γ) and EGFR. Results: There were no significant differences in the expression of IL-1, IL-6, TNF-α, PPAR-γ and EGFR between (a) groups treated with an EGFR inhibitor or an EGFR ligand and (b) the control group, except for a significant increase in the expression of IL-1 in the EGF-treated group. Conclusion: EGFR inhibitors and EGFR ligands do not provoke the expression of inflammatory biomarkers in cultured sebocytes. The role of the sebaceous glands in EGFR inhibitor-induced acneiform eruption should be investigated more thoroughly. (Ann Dermatol 23(1) 12∼18, 2011)

show abstract

The β2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms

Cited by 78 publications

References 60 publications

The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells

The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells

Plant Polyphenols Regulate Chemokine Expression and Tissue Repair in Human Keratinocytes Through Interaction with Cytoplasmic and Nuclear Components of Epidermal Growth Factor Receptor System

Treatment of Cultured Sebocytes with an EGFR Inhibitor Does Not Lead to Significant Upregulation of Inflammatory Biomarkers

Contact Info

Product

Resources

About