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.bone.2010.03.021

Cited by 52 publications

(31 citation statements)

References 47 publications

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“…Ectopic expression of the FGFR3 mutants results in their activation via spontaneous dimerization, with the activating potential of the given mutation easily appreciated by the level of ERK phosphorylation (Fig. 6A) [12]. We also demonstrate the Thr1572 phosphorylation of LRP6, which took place in cells expressing highly activating FGFR3 mutants R248C and K650E (Fig.…”

Section: Resultssupporting

confidence: 51%

Receptor Tyrosine Kinases Activate Canonical WNT/β-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct β-Catenin Phosphorylation

et al. 2012

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Receptor tyrosine kinase signaling cooperates with WNT/β-catenin signaling in regulating many biological processes, but the mechanisms of their interaction remain poorly defined. We describe a potent activation of WNT/β-catenin by FGFR2, FGFR3, EGFR and TRKA kinases, which is independent of the PI3K/AKT pathway. Instead, this phenotype depends on ERK MAP kinase-mediated phosphorylation of WNT co-receptor LRP6 at Ser1490 and Thr1572 during its Golgi network-based maturation process. This phosphorylation dramatically increases the cellular response to WNT. Moreover, FGFR2, FGFR3, EGFR and TRKA directly phosphorylate β-catenin at Tyr142, which is known to increase cytoplasmic β-catenin concentration via release of β-catenin from membranous cadherin complexes. We conclude that signaling via ERK/LRP6 pathway and direct β-catenin phosphorylation at Tyr142 represent two mechanisms used by various receptor tyrosine kinase systems to activate canonical WNT signaling.

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Section: Resultssupporting

confidence: 51%

Receptor Tyrosine Kinases Activate Canonical WNT/β-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct β-Catenin Phosphorylation

et al. 2012

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“…As mentioned above, a positive correlation between RAS expression and A-type lamin expression was found in human seminomas [ 16 ]. In parallel to these results, a recent study showed that in osteoblast differentiation by FGF3 activation, leading to RAS and ERK activation, expression of lamin A/C is increased [ 45 ]. As for SCLC, the mechanism by which increased LMNA expression is achieved upon RAS activation is unclear so far.…”

Section: Lung Cancer Cell Linesmentioning

confidence: 54%

“…It is known that v-Ha-RAS can cause proliferation in some cells and senescence induction in other cells. In the SCLC cell line NCI-H249 it seems that v-Ha-RAS expression leads to a cell phenotype with both increased growth and increased levels of differentiation [ 47 ], accompanied by an increase in lamin A/C expression [ 43 ], while, as mentioned above, in osteoblasts, enhanced normal RAS expression causes differentiation and senescence [ 45 ]. …”

Section: Lung Cancer Cell Linesmentioning

confidence: 99%

The Role of the Nuclear Lamina in Cancer and Apoptosis

Broers

Ramaekers

2014

Advances in Experimental Medicine and Biology

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Not long after the discovery of lamin proteins, it became clear that not all lamin subtypes are ubiquitously expressed in cells and tissues. Especially, A-type lamins showed an inverse correlation with proliferation and were thus initially called statins. Here we compare the findings of both A- and B-type lamin expression in various normal tissues and their neoplastic counterparts. Based on immunocytochemistry it becomes clear that lamin expression patterns are much more complicated than initially assumed: while normally proliferative cells are devoid of A-type lamin expression, many neoplastic tissues do show prominent A-type lamin expression. Conversely, cells that do not proliferate can be devoid of lamin expression. Yet, within the different types of tissues and tumors, lamins can be used to distinguish between tumor subtypes. The link between the appearance of A-type lamins in differentiation and the appearance of A-type lamins in a tumor likely relates the proliferative capacity of the tumor to its differentiation state.While lamins are targets for degradation in the apoptotic process, and accordingly are often used as markers for apoptosis, intriguing studies on an active role of lamins in the initiation or the prevention of apoptosis have been published recently and give rise to a renewed interest in the role of lamins in cancer.

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“…Sustained activation of ERK can induce cell senescence. A study [82] using rat chondrosarcoma cells demonstrated that sustained ERK activation mediated by FGFR3 promoted the expression of the senescent phenotype markers. Extracellular ROS could also contribute to inhibition of the Akt pathway through oxidized low-density lipoprotein (LDL).…”

Section: Chondrocyte Changesmentioning

confidence: 99%

The Age-Related Changes in Cartilage and Osteoarthritis

Wei

Zhou

et al. 2013

BioMed Research International

124

119

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Osteoarthritis (OA) is closely associated with aging, but its underlying mechanism is unclear. Recent publications were reviewed to elucidate the connection between aging and OA. With increasing OA incidence, more senior people are facing heavy financial and social burdens. Age-related OA pathogenesis is not well understood. Recently, it has been realized that age-related changes in other tissues besides articular cartilage may also contribute to OA development. Many factors including senescence-related secretory phenotypes, chondrocytes' low reactivity to growth factors, mitochondrial dysfunction and oxidative stress, and abnormal accumulation of advanced glycation end products (AGEs) may all play key roles in the pathogenesis of age-related OA. Lately, epigenetic regulation of gene expression was recognized for its impact on age-related OA pathogenesis. Up to now, few studies have been reported about the role of miRNA and long-noncoding RNA (lncRNA) in age-related OA. Research focusing on this area may provide valuable insights into OA pathogenesis. OA-induced financial and social burdens have become an increasingly severe threat to older population. Age-related changes in noncartilage tissue should be incorporated in the understanding of OA development. Growing attention on oxidative stress and epigenetics will provide more important clues for the better understanding of the age-related OA.

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

Cited by 52 publications

References 47 publications

Receptor Tyrosine Kinases Activate Canonical WNT/β-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct β-Catenin Phosphorylation

Receptor Tyrosine Kinases Activate Canonical WNT/β-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct β-Catenin Phosphorylation

The Role of the Nuclear Lamina in Cancer and Apoptosis

The Age-Related Changes in Cartilage and Osteoarthritis

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