FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence

Krejčı́, Pavel; Procházková, Jiřina; Smutny, Jiri; Chlebová, Katarina; Lin, Patricia; Aklian, Anie; Bryja, Vı́tězslav; Kozubı́k, Alois; Wilcox, William R.

doi:10.1016/j.ydbio.2010.05.341

Cited by 3 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In previous studies, overexpression of ATG5 in cells or mice was found to accelerate LC3 puncta and formation of autophagic vacuoles, 50,51 we then asked whether transient overexpression of ATG5 can rescue the activated FGFR3-mediated inhibition on chondrocyte viability and differentiation. In this study, our MTT assay and cell counting results showed that overexpression of FGFR3 Y373C markedly suppressed the cell viability of RCS cells by 15% and 29%, respectively, which is consist with a previous report, 52 meanwhile, overexpression of ATG5 alleviated the inhibition on cell viability (Fig. 7E).…”

Section: Fgfr3 Interacts With the Atg12-atg5 Conjugate In Cells And Isupporting

confidence: 92%

FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12–ATG5 conjugate, leading to the delay of cartilage development in achondroplasia

Wang

et al. 2015

Autophagy

View full text Add to dashboard Cite

(2015) FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12-ATG5 conjugate, leading to the delay of cartilage development in achondroplasia, Autophagy, 11:11, 1998, DOI: 10.1080/15548627.2015 G369C/C , constitutively active Fgfr3 mice; ATG5, autophagy-related 5; ATG12, autophagy-related 12; coIP, coimmunoprecipitation; CTGF/CCN2, connective tissue growth factor; FGFR3, fibroblast growth factor receptor 3; FGF, fibroblast growth factor; K D , kinase domain; PBS, phosphate-buffered saline; R3CKO, fgfr3 flox/flox mice, Fgfr3 conditional knockout mice; R3KO mice, fgfr3 global knockout mice; RCS, rat chondrosarcoma; Sumf1, sulfatase modifying factor 1; TM, 4-hydroxy tamoxifen; WT, wild type; YFP-PCA, yellow fluorescent protein-based protein-fragment complementation assay.FGFR3 (fibroblast growth factor receptor 3) is a negative regulator of endochondral ossification. Gain-of-function mutations in FGFR3 are responsible for achondroplasia, the most common genetic form of dwarfism in humans. Autophagy, an evolutionarily conserved catabolic process, maintains chondrocyte viability in the growth plate under stress conditions, such as hypoxia and nutritional deficiencies. However, the role of autophagy and its underlying molecular mechanisms in achondroplasia remain elusive. In this study, we found activated FGFR3 signaling inhibited autophagic activity in chondrocytes, both in vivo and in vitro. By employing an embryonic bone culture system, we demonstrated that treatment with autophagy inhibitor 3-MA or chloroquine led to cartilage growth retardation, which mimics the effect of activated-FGFR3 signaling on chondrogenesis. Furthermore, we found that FGFR3 interacted with ATG12-ATG5 conjugate by binding to ATG5. More intriguingly, FGFR3 signaling was found to decrease the protein level of ATG12-ATG5 conjugate. Consistently, using in vitro chondrogenic differentiation assay system, we showed that the ATG12-ATG5 conjugate was essential for the viability and differentiation of chondrocytes. Transient transfection of ATG5 partially rescued FGFR3-mediated inhibition on chondrocyte viability and differentiation. Our findings reveal that FGFR3 inhibits the autophagic activity by decreasing the ATG12-ATG5 conjugate level, which may play an essential role in the pathogenesis of achondroplasia.

show abstract

Section: Fgfr3 Interacts With the Atg12-atg5 Conjugate In Cells And Isupporting

confidence: 92%

FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12–ATG5 conjugate, leading to the delay of cartilage development in achondroplasia

Wang

et al. 2015

Autophagy

View full text Add to dashboard Cite

show abstract

“…To assess FGF biological activity, we compared their effect on proliferation of rat chondrosarcoma (RCS) chondrocytes which responds to addition of exogenous FGF with potent growth arrest and characteristic changes in cellular morphology [25,26]. We obtained growth curves of cells treated with 1-20 ng/ml of all 18 members of the FGF family.…”

Section: Resultsmentioning

confidence: 99%

Instability restricts signaling of multiple fibroblast growth factors

Buchtová

Chaloupková

Zakrzewska

et al. 2015

Cell. Mol. Life Sci.

Self Cite

View full text Add to dashboard Cite

Fibroblast growth factors (FGFs) deliver extracellular signals that govern many developmental and regenerative processes, but the mechanisms regulating FGF signaling remain incompletely understood. Here, we explored the relationship between intrinsic stability of FGF proteins and their biological activity for all 18 members of the FGF family. We report that FGF1, FGF3, FGF4, FGF6, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and FGF22 exist as unstable proteins, which are rapidly degraded in cell cultivation media. Biological activity of FGF1, FGF3, FGF4, FGF6, FGF8, FGF10, FGF16, FGF17, and FGF20 is limited by their instability, manifesting as failure to activate FGF receptor signal transduction over long periods of time, and influence specific cell behavior in vitro and in vivo. Stabilization via exogenous heparin binding, introduction of stabilizing mutations or lowering the cell cultivation temperature rescues signaling of unstable FGFs. Thus, the intrinsic ligand instability is an important elementary level of regulation in the FGF signaling system.

show abstract

“…As shown here, we see differences in the cohorts of cell cycle markers (p21, p16) in the senescent-like phenotype. In addition, growth factor signaling through receptors such as FGFR3 may also contribute to a reversible form of cellular senescence (Krejci et al, 2010). Together, these data indicate that SAb-galactosidase is an unreliable marker of true senescence, and we may need to rely more heavily on genetic markers such as p16 and p21, as well as measure other factors, including the rate of invasion and Wnt5A expression, to truly assess senescence in the laboratory or in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Wnt5A promotes an adaptive, senescent‐like stress response, while continuing to drive invasion in melanoma cells

Webster

Kinzler

et al. 2014

Pigment Cell Melanoma Res

View full text Add to dashboard Cite

We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAFV600E mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated β-galactosidase (SA-β-gal), senescence associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence like SA-β-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail-vein colony forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance.

show abstract

FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence

Cited by 3 publications

References 0 publications

FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12–ATG5 conjugate, leading to the delay of cartilage development in achondroplasia

FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12–ATG5 conjugate, leading to the delay of cartilage development in achondroplasia

Instability restricts signaling of multiple fibroblast growth factors

Wnt5A promotes an adaptive, senescent‐like stress response, while continuing to drive invasion in melanoma cells

Contact Info

Product

Resources

About