Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of gene loci have recently been shown to harbor mutations that cause human chondrodysplasias. They encode proteins that occupy cartilage matrix, such as types II, IX, X and XI collagens and COMP, that transduce signals in the growth plate, i.e., FGFR3 and PTHrP receptor, that influence the transport and metabolism of sulfate ions in relevant cells, e.g., DTDST and arylsulfatase E, and that regulate transcription of other genes, such as SOX9. Mutations at two loci, COL2A1 and FGFR3, account for most patients with chondrodysplasias--those with spondyloepiphyseal dysplasia and the achondroplasia classes of disorders, respectively. Mutations in the former tend to be dispersed throughout the gene and in other functionally related genes, whereas mutations in the latter are restricted to a few codons that seem to be very mutable.
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PMID:Molecular genetics of the human chondrodysplasias-1995. 882 78

Recently, we demonstrated that loss of Fgf9 results in a block of testis development and a male to female sex-reversed phenotype; however, the function of Fgf9 in sex determination was unknown. We now show that Fgf9 is necessary for two steps of testis development just downstream of the male sex-determining gene, Sry: (1) for the proliferation of a population of cells that give rise to Sertoli progenitors; and (2) for the nuclear localization of an FGF receptor (FGFR2) in Sertoli cell precursors. The nuclear localization of FGFR2 coincides with the initiation of Sry expression and the nuclear localization of SOX9 during the early differentiation of Sertoli cells and the determination of male fate.
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PMID:Fgf9 induces proliferation and nuclear localization of FGFR2 in Sertoli precursors during male sex determination. 1522 80

Biodegradable elastic hydrogel scaffolds based on hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(epsilon-caprolactone) (PCL) were fabricated and investigated as a delivery vehicle of rabbit chondrocytes for the formation of neocartilage. The diacrylated forms of PEG and PCL were used as building blocks to prepare a series of hydrogel scaffolds with different block compositions and, thus, different physico-chemical properties. The porous hydrogel scaffolds were prepared by using the salt leaching method that is generally used for the creation of porous scaffolds, and their in vitro cell interactions were examined using chondrocytes. The hydrogel scaffold with a relatively high PEG content showed better cell growth for chondrocytes, while the scaffold with a relatively low PEG content showed lower chondrogenic differentiation. It was observed that different kinds of scaffolds and rabbit chondrocytes were shown to have different swelling ratios in the scaffold for effective cell growth and tissue regeneration. RT-PCR results for the resultant cartilage tissue revealed that a PEG-PCL ratio of 14 to 6 scaffold was optimal for cartilage tissue formation in terms of collagen Type II, aggrecan, SOX9, and COMP gene expression. In addition, the hydrogel scaffold with a PEG-PCL ratio of 14 to 6 showed faster formation of new cartilage than those shown by other scaffolds.
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PMID:In vitro and in vivo test of PEG/PCL-based hydrogel scaffold for cell delivery application. 1790 79

In mammals, sex is determined in the bipotential embryonic gonad by a balanced network of gene actions which when altered causes disorders of sexual development (DSD, formerly known as intersex). In the XY gonad, presumptive Sertoli cells begin to differentiate when SRY up-regulates SOX9, which in turn activates FGF9 and PGDS to maintain its own expression. This study identifies a new and essential component of FGF signaling in sex determination. Fgfr2 mutant XY mice on a mixed 129/C57BL6 genetic background had either normal testes, or developed ovotestes, with predominantly testicular tissue. However, backcrossing to C57BL6 mice resulted in a wide range of gonadal phenotypes, from hypoplastic testes to ovotestes with predominantly ovarian tissue, similar to Fgf9 knockout mice. Since typical male-specific FGF9-binding to the coelomic epithelium was abolished in Fgfr2 mutant XY gonads, these results suggest that FGFR2 acts as the receptor for FGF9. Pgds and SOX9 remained expressed within the testicular portions of Fgfr2 mutant ovotestes, suggesting that the Prostaglandin pathway acts independently of FGFR2 to maintain SOX9 expression. We could further demonstrate that double-heterozygous Fgfr2/Sox9 knockout mice developed ovotestes, demonstrating that both Fgfr2 and Sox9 can act as modifier intersex genes in the heterozygous state. In summary, we provide evidence that FGFR2 is important for male sex determination in mice, thereby rendering human FGFR2 a candidate gene for unsolved DSD cases such as 10q26 deletions.
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PMID:Loss of Fgfr2 leads to partial XY sex reversal. 1815 90

Although transcriptional control is key for proper lung development, little is known about the possible accompanying epigenetic modifications. Here, we have used gene expression profiling to identify 99 genes that are upregulated in fetal lung and 354 genes that are upregulated in adult lung. From the differentially expressed genes, we analyzed the accompanying 5'-UTR methylation profiles of 43 genes. Out of these, nine genes (COL11A1, MEOX2, SERPINE2, SOX9, FBN2, MDK, COL1A1, LAPTM5 and MARCO) displayed an inverse correlation of their 5'-UTR methylation and the cognate gene expression, suggesting that these genes are at least partially regulated by DNA methylation. Using the differential gene expression/DNA methylation profiles as a guidepost, we identified four genes (MEOX2, MDK, LAPTM5, FGFR3) aberrantly methylated in lung cancer. MEOX2 was uniformly higher methylated in all lung cancer samples (n=15), while the methylation of the other three genes was correlated with either the differentiation state of the tumor (MDK, LAPTM5) or the tumor type itself (FGFR3).
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PMID:Correlative gene expression and DNA methylation profiling in lung development nominate new biomarkers in lung cancer. 1820 46

The intracellular signaling cascade triggered as a result of the surface chemistry of the bone mineral hydroxyapatite (HA) remains largely unknown. In this study, we found that the ERK signaling molecule is activated in response to HA. Moreover, we have performed the first systemic analysis of expression profiles using microarray technology. Eleven genes, including those involved in calcium regulation and bone matrix formation, showed a greater than 2.0-fold change in expression level in response to HA. Among those genes upregulated by HA was the gene encoding SOX9, whose expression we confirmed by real-time PCR analysis with a 5.7-fold increase in expression. Taken together, our results suggest that the activation of ERK and SOX9 by HA could have important implications for understanding the mechanisms by which cells respond on a molecular level to HA.
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PMID:Signaling responses of osteoblast cells to hydroxyapatite: the activation of ERK and SOX9. 1830 69

Longitudinal growth of bone depends on the proliferation and differentiation of chondrocytes located in growth plate. Recent advances in understanding the process of chondrocyte proliferation and differentiation reveal the local and systemic factors responsible for the process. SOX9, Ihh and FGFR3 are the former, growth hormone and thyroid hormone the latter. Achondroplasia, a representative entity of skeletal dysplasia is caused by the abnormality of FGFR3 and exhibits short stature. Hypofunction of growth hormone and thyroid hormone are associated with short stature as well.
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PMID:[Mechanism of bone and cartilage growth during childhood and growth disorders]. 1844 90

Preadipocyte factor-1 [Pref-1; also called Dlk1 (Delta-like protein 1)] is made as an epidermal growth factor-repeat containing transmembrane protein that produces a biologically active soluble form by TNF-alpha-converting enzyme (TACE)-mediated cleavage. Soluble Pref-1 activates the MAPK kinase/ERK pathway. In adipose tissue, Pref-1 is specifically expressed in preadipocytes but not in adipocytes and thus is used as a preadipocyte marker. Inhibition of adipogenesis by Pref-1 has been well established in vitro as well as in vivo by ablation and overexpression of Pref-1. SRY (sex determining region Y)-box 9 (Sox9), a transcription factor expressed in preadipocytes to suppress CCAAT enhancer binding protein beta and (C/EBP) delta expression, is required to be down-regulated before adipocyte differentiation can proceed. By activating MAPK kinase/ERK, Pref-1 prevents down-regulation of Sox9, resulting in inhibition of adipogenesis. Furthermore, by inducing Sox9, Pref-1 promotes chondrogenic induction of mesenchymal cells but prevents chondrocyte maturation as well as osteoblast differentiation. Thus, Pref-1 directs multipotent mesenchymal cells toward the chondrogenic lineage but inhibits differentiation into adipocytes as well as osteoblasts and chondrocytes. Pref-1, encoded by an imprinted gene, has also been detected in progenitor cells in various tissues during regeneration and therefore may have a more general role in maintaining cells in an undifferentiated state.
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PMID:Minireview: Pref-1: role in adipogenesis and mesenchymal cell fate. 1954 43

Few surface markers are available to monitor lineage differentiation during chondrogenesis. Recently, delta-like1/fetal antigen1 (dlk1/FA1), a transmembrane protein of the Notch/Delta/Serrata family, was shown to be essential for inducing early chondrogenesis. Thus, we investigated the possible use of dlk1/FA1 as a novel surface marker for chondroprogenitor cells during hESC differentiation. We found that, Dlk1/FA1 is expressed specifically in cells undergoing transition from proliferating to prehypertrophic chondrocytes during endochondral ossification of the mouse limb. In hESC cells, dlk1/FA1 was not expressed by undifferentiated hESC, but expressed during in vitro embryoid bodies (hEBs) formation upon down-regulation of undifferentiated markers e.g. Oct 3/4. Similarly, dlk1/FA1 was expressed in chondrocytic cells during in vivo teratoma formation. Interestingly, treatment of hEBs with Activin B, a member of TGF-ss family, markedly increased Dlk1 expression in association with up-regulation of the mesoderm-specific markers (e.g. FOXF1, KDR and VE-cadherin) and SOX9. dlk1/FA1(+) cells isolated by fluorescence activated cell sorting (FACS) were capable of differentiating into chondrocytic cells when cultured as micromass pellets in a xeno-free system containing TGFbeta1. In conclusion, we identified dlk1/FA1 as a novel marker of chondroprogenitor cells that undergo embryonic lineage progression from proliferation to the prehypertrophic stage. Tracking dlk1/FA1 expression as a mesoderm/chondroprogenitor surface marker provides a novel strategy for designing clinically relevant protocols to direct the differentiation of hESC into chondrocytes.
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PMID:Isolation and differentiation of chondrocytic cells derived from human embryonic stem cells using dlk1/FA1 as a novel surface marker. 2005

The high-density micromass culture has been widely applied to study chondrocyte cell physiology and pathophysiological mechanisms. Since an integrated image has not been established so far, we analyzed the phenotypic alterations of human articular chondrocytes in this model on the broad molecular level. Freshly isolated chondrocytes were assembled as micromasses and maintained up to 6 weeks in medium containing human serum. Formation of cartilaginous extracellular matrix (ECM) was evaluated by histological and immunohistochemical staining. At 0, 3 and 6 weeks, chondrocyte micromasses were subjected to gene expression analysis using oligonucleotide microarrays and real-time RT-PCR. Micromasses developed a cartilaginous ECM rich in proteoglycans and type II collagen. On gene expression level, time-dependent expression patterns was observed. The induction of genes associated with cartilage-specific ECM (COL2A1 and COL11A1) and developmental signaling (GDF5, GDF10, ID1, ID4 and FGFR1-3) indicated redifferentiation within the first 3 weeks. The repression of genes related to stress response (HSPA1A and HSPA4), apoptotic events (HYOU1, NFKBIA and TRAF1), and degradation (MMP1, MMP10 and MMP12) suggested a recovery of chondrocytes. Constant expression of other chondrogenic (ACAN, FN1 and MGP) and hypertrophic markers (COL10A1, ALPL, PTHR1 and PTHR2) indicated a pattern of phenotypic maintenance. Simultaneously, the expression of chondrogenic growth (BMP6, TGFA, FGF1 and FGF2) and transcription factors (SOX9, EGR1, HES1 and TGIF1), and other cartilage ECM-related genes (COMP and PRG4) was consistently repressed and expression of collagens related to dedifferentiation (COL1A1 and COL3A1) was steadily induced indicating a progressing loss of cartilage phenotype. Likewise, a steady increase of genes associated with proliferation (GAS6, SERPINF1, VEGFB and VEGFC) and apoptosis (DRAM, DPAK1, HSPB, GPX1, NGFRAP1 and TIA1) was observed. Sequence and interplay of identified expression patterns suggest that chondrocyte micromass cultures maintain a differentiated phenotype up to 3 weeks in vitro and might be useful for studying chondrocyte biology, pathophysiology and differentiation. Cultivation longer than 6 weeks leads to progressing dedifferentiation of chondrocytes that should be considered on long-term evaluations.
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PMID:Gene expression profiling of primary human articular chondrocytes in high-density micromasses reveals patterns of recovery, maintenance, re- and dedifferentiation. 2043 12


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