Transitory FGF Treatment Results in the Long‐Lasting Suppression of the Proliferative Response to Repeated FGF Stimulation

Poole, Ashleigh; Knowland, Nicholas; Cooper, Emily; Cole, R. N.; Wang, Hongchuan; Booth, Lucas; Kacer, Doreen; Tarantini, Francesca; Friesel, Robert; Prudovsky, Igor

doi:10.1002/jcb.24731

Cited by 5 publications

(11 citation statements)

References 32 publications

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“…FGF memory could be dependent on HDAC‐mediated histone deacetylation or on HDAC‐dependent activation of NFκB signaling or on both. As we have reported (Poole et al, ), FGF does not change the expression of major HDACs. Thus, the search for a specific HDAC involved in FGF1 memory followed by the identification of its mechanism of action requires a comprehensive siRNA knockdown screen study involving the assessment of FGF memory establishment, NFκB signaling activity and IL1α expression.…”

Section: Discussionsupporting

confidence: 83%

“…We have earlier reported that transient FGF stimulation results in a sustained activation of NFκB signaling, which is critical for FGF memory establishment (Poole et al, ). IL1α (Niu et al, ; Melisi et al, ) and FGF (Muddasani et al, ; Salazar et al, ) have been demonstrated to activate the proinflammatory NFκB pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The observations that FGF stimulation activates NFkB signaling, and establishment of FGF memory depends on NFkB pathway (Poole et al, 2014) indicated that FGF may induce the expression of a proinflammatory cytokine. Interestingly, IL1a, a potent inducer of inflammation and activator of NFkB signaling, represses cell proliferation (Ohmori et al, 1988;Ikeda et al, 1991) and plays a key role in some cases of cell senescence (Maier et al, 1990;McCarthy et al, 2013).…”

Section: Fgf Induces the Expression Of Il1amentioning

confidence: 99%

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Sustained Inhibition of Proliferative Response After Transient FGF Stimulation Is Mediated by Interleukin 1 Signaling

Poole

Kacer

Cooper

et al. 2015

Journal Cellular Physiology

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Transient FGF stimulation of various cell types results in FGF memory – a sustained blockage of efficient proliferative response to FGF and other growth factors. FGF memory establishment requires HDAC activity, indicating its epigenetic character. FGF treatment stimulates proinflammatory NFκB signaling, which is also critical for FGF memory formation. The search for FGF-induced mediators of FGF memory revealed that FGF stimulates HDAC-dependent expression of the inflammatory cytokine IL1α. Similarly to FGF, transient cell treatment with recombinant IL1α inhibits the proliferative response to further FGF and EGF stimulation, but does not prevent FGF receptor-mediated signaling. Interestingly, like cells pretreated with FGF1, cells pretreated with IL1α exhibit enhanced restructuring of actin cytoskeleton and increased migration in response to FGF stimulation. IRAP, a specific inhibitor of IL1 receptor, and a neutralizing anti-IL1α antibody prevent the formation of FGF memory and rescue an efficient proliferative response to FGF restimulation. A similar effect results following treatment with the anti-inflammatory agents aspirin and dexamethasone. Thus, FGF memory is mediated by proinflammatory IL1 signaling. It may play a role in the limitation of proliferative response to tissue damage and prevention of wound-induced hyperplasia.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Fgf Induces the Expression Of Il1amentioning

confidence: 99%

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Sustained Inhibition of Proliferative Response After Transient FGF Stimulation Is Mediated by Interleukin 1 Signaling

Poole

Kacer

Cooper

et al. 2015

Journal Cellular Physiology

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“…Importantly however, the precedence of the transient induction of heritable changes after removing a stimulus has already been linked to the epithelial-to-mesenchymal transition process, creating self-renewing breast cancer stem cells from a nonstem cell population [60,61]. In another study, a "memory" of transitory FGF had a long-lasting effect on the fibroblast response to the secondary FGF stimulation; this memory reduced rather than increased their proliferation [62]. These findings underscore epigenetics and chromatin structure in controlling long-term responses, including the generation of CSCs and their phenotypic plasticity [63].…”

Section: Discussionmentioning

confidence: 99%

Transient TNF regulates the self-renewing capacity of stem-like label-retaining cells in sphere and skin equivalent models of melanoma

Ostyn

Machhour

Bégard

et al. 2014

Cell Communication and Signaling

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Background: It is well established that inflammation promotes cancer, including melanoma, although the exact mechanisms involved are less known. In this study, we tested the hypothesis that inflammatory factors affect the cancer stem cell (CSC) compartment responsible for tumor development and relapse. Results: Using an inducible histone 2B-GFP fusion protein as a tracer of cell divisional history, we determined that tumor necrosis factor (TNF), which is a classical pro-inflammatory cytokine, enlarged the CSC pool of GFP-positive label-retaining cells (LRCs) in tumor-like melanospheres. Although these cells acquired melanoma stem cell markers, including ABCB5 and CD271, and self-renewal ability, they lost their capacity to differentiate, as evidenced by the diminished MelanA expression in melanosphere cells and the loss of pigmentation in a skin equivalent model of human melanoma. The undifferentiated cell phenotype could be reversed by LY294002, which is an inhibitor of the PI3K/AKT signaling pathway, and this reversal was accompanied by a significant reduction in CSC phenotypic markers and functional properties. Importantly, the changes induced by a transient exposure to TNF were long-lasting and observed for many generations after TNF withdrawal.

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“…We have previously reported that repeated FGF1 stimulation also suppresses the proliferative response of endothelial cells and fibroblasts, a phenomenon we have coined as “FGF1 memory” (Poole et al. , ). Together, these data strongly suggest that continuous or prolonged FGF1 exposure suppresses preadipocyte self‐renewal and/or the adipogenesis process itself.…”

Section: Discussionmentioning

confidence: 99%

Resistance to visceral obesity is associated with increased locomotion in mice expressing an endothelial cell‐specific fibroblast growth factor 1 transgene

et al. 2019

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Overdevelopment of visceral adipose is positively correlated with the etiology of obesity‐associated pathologies including cardiovascular disease and insulin resistance. However, identification of genetic, molecular, and physiological factors regulating adipose development and function in response to nutritional stress is incomplete. Fibroblast Growth Factor 1 ( FGF 1) is a cytokine expressed and released by both adipocytes and endothelial cells under hypoxia, thermal, and oxidative stress. Expression of Fibroblast Growth Factor 1 ( FGF 1) in adipose is required for normal depot development and remodeling. Loss of FGF 1 leads to deleterious changes in adipose morphology, metabolism, and insulin resistance. Conversely, diabetic and obese mice injected with recombinant FGF 1 display improvements in insulin sensitivity and a reduction in adiposity. We report in this novel, in vivo study that transgenic mice expressing an endothelial‐specific FGF 1 transgene ( FGF 1‐Tek) are resistant to high‐fat diet‐induced abdominal adipose accretion and are more glucose‐tolerant than wild‐type control animals. Metabolic chamber analyses indicate that suppression of the development of visceral adiposity and insulin resistance was not associated with alterations in appetite or resting metabolic rate in the FGF 1‐Tek strain. Instead, FGF 1‐Tek mice display increased locomotor activity that likely promotes the utilization of dietary fatty acids before they can accumulate in adipose and liver. This study provides insight into the impact that genetic differences dictating the production of FGF 1 has on the risk for developing obesity‐related metabolic disease in response to nutritional stress.

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Transitory FGF Treatment Results in the Long‐Lasting Suppression of the Proliferative Response to Repeated FGF Stimulation

Cited by 5 publications

References 32 publications

Sustained Inhibition of Proliferative Response After Transient FGF Stimulation Is Mediated by Interleukin 1 Signaling

Sustained Inhibition of Proliferative Response After Transient FGF Stimulation Is Mediated by Interleukin 1 Signaling

Transient TNF regulates the self-renewing capacity of stem-like label-retaining cells in sphere and skin equivalent models of melanoma

Resistance to visceral obesity is associated with increased locomotion in mice expressing an endothelial cell‐specific fibroblast growth factor 1 transgene

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