The STAT3-IGFBP5 axis is critical for IL-6/gp130-induced premature senescence in human fibroblasts

Kojima, Hiroyuki; Kunimoto, Hiroyuki; Inoue, Toshiaki; Nakajima, Kōichi

doi:10.4161/cc.11.4.19172

Cited by 88 publications

(74 citation statements)

References 44 publications

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“…One component of the SASP that is capable of triggering a DDR in a paracrine manner is TGF‐β1, raising the possibility that signaling through the TGF‐β receptor causes a DDR by promoting telomere dysfunction (Dickey et al, 2009; Hubackova et al, 2012; Kojima, Kunimoto, Inoue, & Nakajima, 2012). Indeed, addition of a specific inhibitor of the TGF‐β receptor I to the culture medium inactivated the telomere dysfunction‐inducing activity of the SASP, suggesting that TGF‐β1 contained within the SASP causes telomere dysfunction in a paracrine manner (Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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Cells that had undergone telomere dysfunction‐induced senescence secrete numerous cytokines and other molecules, collectively called the senescence‐associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF‐β1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS‐dependent manner. Surprisingly, instead of activating cellular senescence, TGF‐β1‐induced telomere dysfunction caused fibroblasts to transdifferentiate into α‐SMA‐expressing myofibroblasts, a mesenchymal and contractile cell type that is critical for wound healing and tissue repair. Despite the presence of dysfunctional telomeres, transdifferentiated cells acquired the ability to contract collagen lattices and displayed a gene expression signature characteristic of functional myofibroblasts. Significantly, the formation of dysfunctional telomeres and downstream p53 signaling was necessary for myofibroblast transdifferentiation, as suppressing telomere dysfunction by expression of hTERT, inhibiting the signaling pathways that lead to stochastic telomere dysfunction, and suppressing p53 function prevented the generation of myofibroblasts in response to TGF‐β1 signaling. Furthermore, inducing telomere dysfunction using shRNA against TRF2 also caused cells to develop features that are characteristic of myofibroblasts, even in the absence of exogenous TGF‐β1. Overall, our data demonstrate that telomere dysfunction is not only compatible with cell functionality, but they also demonstrate that the generation of dysfunctional telomeres is an essential step for transdifferentiation of human fibroblasts into myofibroblasts.

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Section: Resultsmentioning

confidence: 99%

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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“…Over-expression of IGFBP5 increases osteoclast formation, associated with increased absorption (Kanatani et al 2000), impairs osteoblast function (Devlin et al 2002), and increases cellular senescence (Kim et al 2007; Kojima et al 2012). Transgenic mice that overexpress IGFBP5 have inhibition of growth, increased neonatal mortality, and reduced female fertility (Salih et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome

et al. 2014

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Background Turner syndrome is a sex chromosome aneuploidy with characteristic malformations. Amniotic fluid, a complex biological material, could contribute to the understanding of Turner syndrome pathogenesis. In this pilot study, global gene expression analysis of cell-free RNA in amniotic fluid supernatant was utilized to identify specific genes/organ systems that may play a role in Turner syndrome pathophysiology. Methods Cell-free RNA from amniotic fluid of five mid-trimester Turner syndrome fetuses and five euploid female fetuses matched for gestational age was extracted, amplified, and hybridized onto Affymetrix® U133 Plus 2.0 arrays. Significantly differentially regulated genes were identified using paired t-tests. Biological interpretation was performed using Ingenuity Pathway Analysis and BioGPS gene expression atlas. Results There were 470 statistically significantly differentially expressed genes identified. They were widely distributed across the genome. XIST was significantly down-regulated (p<0.0001); SHOX was not differentially expressed. One of the most highly represented organ systems was the hematologic/immune system, distinguishing the Turner syndrome transcriptome from other aneuploidies we previously studied. Manual curation of the differentially expressed gene list identified genes of possible pathologic significance, including NFATC3, IGFBP5, and LDLR. Conclusions Transcriptomic differences in the amniotic fluid of Turner syndrome fetuses are due to genome-wide dysregulation. The hematologic/immune system differences may play a role in early-onset autoimmune dysfunction. Other genes identified with possible pathologic significance are associated with cardiac and skeletal systems, which are known to be affected in females with Turner syndrome. The discovery-driven approach described here may be useful in elucidating novel mechanisms of disease in Turner syndrome.

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“…The fact that JAK2 might inhibit tumor initiation is not that surprising taking into account for example its activation by interferon, a well known antitumor factor with prosenescence activity (36)(37)(38)(39)(40) or its activation by other known regulator of senescence such as IL6 (41,42). In addition, some components of the JAK signaling, such as JAK1, STAT1, STAT3, and STAT5A, are induced and involved during the senescence program (43)(44)(45)(46). JAK2 signaling might thus exert a dual role on cell growth and cancer.…”

Section: Discussionmentioning

confidence: 99%

PLA2R1 Mediates Tumor Suppression by Activating JAK2

et al. 2013

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Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor, the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Furthermore, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This finding was unexpected as the JAK2 pathway has been associated mainly with protumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling. Cancer Res; 73(20); 6334-45. Ó2013 AACR.

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The STAT3-IGFBP5 axis is critical for IL-6/gp130-induced premature senescence in human fibroblasts

Cited by 88 publications

References 44 publications

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome

PLA2R1 Mediates Tumor Suppression by Activating JAK2

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