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Journal of Cellular Physiology    [4 followers]  Follow    
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 0021-9541 - ISSN (Online) 1097-4652
     Published by John Wiley and Sons Homepage  [1594 journals]   [SJR: 1.608]   [H-I: 118]
  • Mouse Matrix Metalloprotease‐1a (Mmp1a) Gives New Insight Into MMP
    • Abstract: Matrix metalloprotease‐1 (MMP1) has been implicated in many human disease processes, however the lack of a well characterized murine homologue has significantly limited the study of MMP1 and the development of MMP‐targeted therapeutics. The discovery of murine Mmp1a in 2001, the functional mouse homologue of MMP1, offers a valuable tool for modeling MMP1‐mediated processes in mice. Variation in physiologic expression levels of Mmp1a in mice as compared to MMP1 in humans highlights the importance of understanding the similarities and differences between the homologues. Recent studies have demonstrated tumor growth‐, invasion‐, and angiogenesis‐promoting functions of Mmp1a in lung cancer models, consistent with the analogous functions observed for human MMP1. Biochemical investigations have shown that point mutations in the pro‐domain of mouse Mmp1a weaken docking between the pro‐ and catalytic domains, generating an unstable zymogen primed for activation. The difficulty to effectively maintain Mmp1a in the zymogen form may account for the tight control of Mmp1a expression and reduced expression in normal tissue as compared to inflammatory states or cancer. This discovery raises important questions about the activation mechanisms and regulation of the MMP family in general. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Mg2+‐dependent Modulation of BKCa Channels by Genistein in Rat
           Arteriolar Smooth Muscle Cells
    • Abstract: Genistein, a protein tyrosine kinase (PTK) inhibitor, regulates ion channel activities. However, the mechanism of action of genistein on large‐conductance calcium‐activated potassium (BKCa) channels is unclear. This study aimed to investigate whether the mechanism of Mg2+‐dependent modulation of BKCa channel activity in vascular smooth muscle cells involved inhibition of phosphorylation by genistein or direct interaction between genistein and BKCa channels. The whole‐cell and inside‐out patch‐clamp techniques were used to measure BKCa currents and the effects of genistein on BKCa channel activities in rat mesenteric arteriolar smooth muscle cells. We found that the effects of genistein on BKCa currents were Mg2+‐dependent. Genistein (50 μM) inhibited BKCa currents if the intracellular free magnesium concentration ([Mg2+]i) was 2 μM or 20 μM, but amplified BKCa currents if [Mg2+]i was 200 μM or 2000 μM. The inhibitory effect of genistein on BKCa currents was reversed by the protein tyrosine phosphatase inhibitor sodium orthovanadate (0.5 mM). Daidzein (50 μM), an inactive analogue of genistein, also amplified BKCa currents, and its amplification was insensitive to orthovanadate. Another PTK inhibitor, tyrphostin 23 (50 μM), reduced the open probability of BKCa channels. This inhibitory effect was weaker at 200 μM [Mg2+]i than at 2 μM [Mg2+]i, and was countered by orthovanadate. Our results suggest that genistein amplifies BKCa currents at a high [Mg2+]i, but inhibits BKCa currents at a low [Mg2+]i. The mechanism of this biphasic effects involves PTK‐independent amplification and [Mg2+]i‐PTK‐dependent inhibition. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Isoforms of Receptors of Fibroblast Growth Factors
    • Abstract: The breadth and scope of Fibroblast Growth Factor signaling is immense, with documentation of its role in almost every organism and system studied so far. FGF ligands signal through a family of four distinct tyrosine kinase receptors, the FGF receptors (FGFRs). One contribution to the diversity of function and signaling of FGFs and their receptors arises from the numerous alternative splicing variants that have been documented in the FGFR literature. The present review discusses the types and roles of alternatively spliced variants of the FGFR family members and the significant impact of alternative splicing on the physiological functions of five broad classes of FGFR isoforms. Some characterized known regulatory mechanisms of alternative splicing and future directions in studies of FGFR alternative splicing are also discussed. Presence, absence, and/or the combination of specific exons within each FGFR protein impart upon each individual isoform its unique function and expression pattern during normal function and in diseased states (e.g., in cancers and birth defects). A better understanding of the diversity of FGF signaling in different developmental contexts and diseased states can be achieved through increased knowledge of the presence of specific FGFR isoforms and their impact on downstream signaling and functions. Modern high‐throughput techniques afford an opportunity to explore the distribution and function of isoforms of FGFR during development and in diseases. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Analysis of Global Changes in Gene Expression Induced by Human
           Polynucleotide Phosphorylase (hPNPaseold‐35 )
    • Abstract: As a strategy to identify gene expression changes affected by human polynucleotide phosphorylase (hPNPaseold‐35 ), we performed gene expression analysis of HeLa cells in which hPNPaseold‐35 was overexpressed. The observed changes were then compared to those of HO‐1 melanoma cells in which hPNPaseold‐35 was stably knocked down. Through this analysis, 90 transcripts, which positively or negatively correlated with hPNPaseold‐35 expression, were identified. The majority of these genes were associated with cell communication, cell cycle, and chromosomal organization gene ontology categories. For a number of these genes, the positive or negative correlations with hPNPaseold‐35 expression were consistent with transcriptional data extracted from the TCGA (The Cancer Genome Atlas) expression datasets for colon adenocarcinoma (COAD), skin cutaneous melanoma (SKCM), ovarian serous cyst adenocarcinoma (OV), and prostate adenocarcinoma (PRAD). Further analysis comparing the gene expression changes between Ad.hPNPaseold‐35 infected HO‐1 melanoma cells and HeLa cells overexpressing hPNPaseold‐35 under the control of a doxycycline‐inducible promoter, revealed global changes in genes involved in cell cycle and mitosis. Overall, this study provides further evidence that hPNPaseold‐35 is associated with global changes in cell cycle‐associated genes and identifies potential gene targets for future investigation. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Beclin‐1 Is Required for RANKL‐Induced Osteoclast
    • Abstract: Beclin‐1 plays a critical role in autophagy; however, it also contributes to other biological processes in a non‐autophagic manner. Although studies have examined the non‐autophagic role of autophagy proteins in the secretory function of osteoclasts (OC), the role of Beclin‐1 is unclear. Here, we examined the role of Beclin‐1 in OC differentiation, and found that mouse bone marrow macrophages (BMMs) showed increased expression of Beclin‐1 upon RANKL stimulation in a p38‐ and NF‐kappa B‐dependent manner. During OC differentiation, Beclin‐1 localized to the mitochondria, where it was involved in the production of mitochondrial intracellular reactive oxygen species. Knockdown of Beclin‐1 in RANKL‐primed BMMs led to a significant reduction in RANKL‐dependent osteoclastogenesis, which was accompanied by reduced NFATc1 induction. Furthermore, knockdown of Beclin‐1 inhibited RANKL‐mediated activation of JNK and p38, both of which act downstream of reactive oxygen species, resulting in the suppression of NFATc1 induction. Finally, overexpression of constitutively active NFATc1 rescued the phenotype induced by Beclin‐1 knockdown, indicating that Beclin‐1 mediates RANKL‐induced osteoclastogenesis by regulating NFATc1 expression. These findings show that Beclin‐1 plays a non‐autophagic role in RANKL‐induced osteoclastogenesis by inducing the production of reactive oxygen species and NFATc1. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Advanced Glycation End Products Induce Lipogenesis: Regulation by Natural
           Xanthone through Inhibition of ERK and NF‐κB
    • Abstract: Advanced glycation end products (AGE) accumulate in diabetic patients and aged persons due to high amounts of 3‐ or 4‐carbon derivatives of glucose. Understanding the mechanism of AGE‐mediated signaling leading to these consequences, like oxidative stress, inflammation, apoptosis, etc. and its regulation would be a viable strategy to control diabetic complication and age‐related diseases. We have detected the probable mechanism by which AGE increases lipogenesis, the cause of fatty liver in diabetic patients. AGE increased lipid accumulation in different cells as shown by Oil Red O staining. AGE‐mediated regulation of several transcription factors was determined by gel shift assay. Antioxidants like NAC, PDTC, and vitamin C, except mangiferin, were unable to protect AGE‐induced activation of SREBP and subsequent lipid accumulation. AGE increased the phosphorylation of ERK, and IKK and also DNA binding ability of SREBP, thereby its dependent gene transcription. AGE induces NF‐κB which might suppress PPARγ activity, in turn reducing lipid breakdown and mobilization. Mangiferin not only inhibits AGE‐mediated ROI generation that requires NF‐κB activation, but also inhibits ERK and IKK activity, thereby suppression of SREBP activity and lipogenesis. Mangiferin has shown a double‐edged sword effect to suppress AGE‐mediated ailments by reducing ROI‐mediated responses as antioxidant and inhibiting SREBP activation thereby lipogenesis, suggesting its potential efficacy against diabetes and obesity‐related diseases. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Inactivation of the LOX‐1 pathway promotes the Golgi apparatus
           during cell differentiation of mural granulosa cells
    • Abstract: In female mammals, granulosa cells of the ovarian follicle differentiate into the corpus luteum after ovulation of the pregnable oocyte into the fallopian tube. During these differentiation processes several morphological alterations have to occur and the molecular basis is not fully understood. As an endpoint estradiol production from granulosa cells has to switch off in favor for progesterone production from the proceeding corpus luteum to sustain the developing embryo. Previously, we demonstrated that the multiligand receptor LOX‐1 plays a critical role in steroid hormone synthesis of granulosa cells via intracellular calcium release from endoplasmic (ER)‐dependent and ER‐independent calcium pools. In the present study, we show that inhibition of LOX‐1 leads to a rearrangement of ceramide from the basal membrane toward the Golgi apparatus. This activity is accomplished by a calcium‐dependent phosphorylation of aromatase, the key step in estradiol production. Phosphorylated aromatase increased estradiol production in a dose‐dependent manner. Our data indicate that the ceramide cascade is essential for proper granulosa cell function and ceramide redistribution serves as a first step in order to proceed with the prosperous differentiation into a corpus luteum. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • CCL27 Is Downregulated by Interferon Gamma via Epidermal Growth Factor
           Receptor in Normal Human Epidermal Keratinocytes
    • Abstract: The cutaneous T cell‐attracting chemokine (CTACK)/CCL27 is indispensable in skin inflammation. CTACK/CCL27 is exclusively produced by epidermal keratinocytes to attract CCR10‐expressing T lymphocytes to the skin. We investigated the mechanism of CTACK/CCL27 production from normal human epidermal keratinocytes (NHEKs) by the proinflammatory cytokines TNFα and IFNγ. CTACK/CCL27 production was induced by TNFα via ERK, JNK, p38, and NFκB. The induction of CTACK/CCL27 by TNFα was suppressed by IFNγ via a pathway dependent on JAK, STAT1, and STAT3. Our results also demonstrated that IFNγ and TNFα induced the phosphorylation of EGFR and the following phosphorylation of ERK, which is partly responsible for the suppressive effect of IFNγ on TNFα‐induced production of CTACK/CCL27. Peri‐lesional skin of psoriasis demonstrates early inflammatory changes as we have previously reported. CTACK/CCL27 expression was diffuse in the peri‐lesional epidermis, while it was restricted to basal layer in lesional epidermis, suggesting that CTACK/CCL27 expression was induced in the early stage of psoriatic plaque formation, and IFNγ could participate in the suppression of CTACK/CCL27 expression in the lesional epidermis, reflecting the later stage of psoriatic plaque formation. Our study suggests that CTACK/CCL27 may have a pivotal role in the early stage of psoriasis plaque formation, but should be downregulated in the later stage to induce inflammation characteristic for chronic psoriasis plaques. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Primary cilium regulates CaV1.2 expression through Wnt signaling
    • Abstract: Primary cilia are sensory organelles that provide a feedback mechanism to restrict Wnt signaling in the absence of endogenous Wnt activators. Abnormal Wnt signaling has been shown to result in polycystic kidney disease (PKD) although the exact mechanism has been debated. Previously, we reported that the calcium channel CaV1.2 functions in primary cilia. In this study, we show that CaV1.2 expression level is regulated by Wnt signaling. This occurs through modulation of mitochondrial mass and activity resulting in increased reactive oxygen species which generate oxidative DNA lesions. We found that the subsequent cellular DNA damage response triggers increased CaV1.2 expression. In the absence of primary cilia where Wnt signaling is upregulated, we found that CaV1.2 is overexpressed as a compensatory mechanism. We show for the first time that CaV1.2 knockdown in zebrafish results in classic primary cilia defects including renal cyst formation, hydrocephalus, and left‐right asymmetry defects. Our study shows that suppressed Wnt signaling prevents CaV1.2 expression ultimately resulting in PKD phenotypes. Thus, CaV1.2 expression is tightly regulated through Wnt signaling and plays an essential sensory role in primary cilia necessary for cellular homeostasis. J. Cell. Physiol. 9999: XX–XX, 2014. © 2014 Wiley Periodicals, Inc.
  • Role of Caspase‐3 Cleaved IP3R1 on Ca2+ Homeostasis and
           Developmental Competence of Mouse Oocytes and Eggs
    • Abstract: Apoptosis in most cell types is accompanied by altered Ca2+ homeostasis. During apoptosis, caspase‐3 mediated cleavage of the type 1 inositol 1,4,5‐trisphosphate receptor (IP3R1) generates a 95‐kDa C‐terminal fragment (C‐IP3R1), which represents the channel domain of the receptor. Aged mouse eggs display abnormal Ca2+ homeostasis and express C‐IP3R1, although whether or not C‐IP3R1 expression contributes to Ca2+ misregulation or a decrease in developmental competency is unknown. We sought to answer these questions by injecting in mouse oocytes and eggs cRNAs encoding C‐IP3R1. We found that: (1) expression of C‐IP3R1 in eggs lowered the Ca2+ content of the endoplasmic reticulum (ER), although, as C‐IP3R1 is quickly degraded at this stage, its expression did not impair pre‐implantation embryo development; (2) expression of C‐IP3R1 in eggs enhanced fragmentation associated with aging; (3) endogenous IP3R1 is required for aging associated apoptosis, as its down‐regulation prevented fragmentation, and expression of C‐IP3R1 in eggs with downregulated IP3R1 partly restored fragmentation; (4) C‐IP3R1 expression in GV oocytes resulted in persistent levels of protein, which abolished the increase in the ER releasable Ca2+ pool that occurs during maturation, undermined the Ca2+ oscillatory ability of matured eggs and their activation potential. Collectively, this study supports a role for IP3R1 and C‐IP3R1 in regulating Ca2+ homeostasis and the ER Ca2+ content during oocyte maturation. Nevertheless, the role of C‐IP3R1 on Ca2+ homeostasis in aged eggs seems minor, as in MII eggs the majority of endogenous IP3R1 remains intact and C‐IP3R1 undergoes rapid turnover. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Hypomethylating Agent 5‐Aza‐2′‐deoxycytidine (DAC)
           Ameliorates Multiple Sclerosis in Mouse Models
    • Abstract: Increasing evidence supports the role of epigenetics in the development of autoimmune disorders and the possibility of using epigenetic modifying drugs in the context of MS has not yet been investigated. We have explored the effect of the hypomethylating agent 5‐aza‐2′‐deoxycytidine (DAC) in two murine models of experimental allergic encephalomyelitis (EAE). DAC treatment was associated with a significant amelioration of the clinical and histological hallmarks of EAE in both models. These effects were observed both in prophylactic and therapeutic regimens. The milder course of the disease was associated with a reduction in the number of spinal cord infiltrating lymphocytes and amelioration of the histopathological signs associated with EAE. In addition, increased transcript levels of anti‐inflammatory cytokines and decreased mRNA expression of pro‐inflammatory mediators were also observed. Finally, DAC treatment increased the percentage of circulating regulatory T cells by inducing Foxp3 expression via demethylation of a CpG island in Foxp3. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Ang II–AT1R Increases Cell Migration Through PI3K/AKT and
           NF‐κB Pathways in Breast Cancer
    • Abstract: Angiotensin II (Ang II), a biologically active peptide of the renin–angiotensin system (RAS), plays an important role in promoting cell migration via Angiotensin II type 1 receptor (AT1R). In this study, we examined the mechanisms by which Ang II affected cell migration in AT1R‐positive MDA‐MB‐231 human breast cancer cells. Ang II increased cell migration and expression of matrix metalloproteinase (MMP)‐2,‐9 in a dose‐dependent manner. Ang II‐mediated cell migration was reduced by specific blocking of MMP‐2 and MMP‐9, as well as with pretreatment with inhibitors of AT1R, phosphatidylinositol 3‐kinase (PI3K), Akt, and NF‐κB. Similarly, Ang II‐mediated expression of MMP‐2,‐9 was downregulated by pretreatment with inhibitors of AT1R and PI3K. In addition, Ang II treatment significantly induced phosphorylation of PI3K, Akt, and resulted in increased NF‐κB activity. These findings suggest that Ang II activates the AT1R/PI3K/Akt pathway, which further activates IKKα/β and NF‐κB, resulting in enhanced expression of MMP‐2,‐9 and migration in human breast cancer cells. Therefore, targeting Ang II/AT1R/PI3K/Akt/NF‐κB signaling could be a novel anti‐metastatic therapy for breast cancer. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Heregulin Negatively Regulates Transcription of ErbB2/3 Receptors via an
           AKT‐Mediated Pathway
    • Abstract: Despite the importance of the ErbB2/3 heterodimer in breast cancer progression, the negative regulation of these receptors is still poorly understood. We demonstrate here for the first time that the ErbB3/4 ligand heregulin (HRG) reduced both ErbB2 and ErbB3 mRNA and protein levels in human breast cancer cell lines. In contrast, EGFR levels were unaffected by HRG treatment. The effect was rapid with a decline in steady‐state mRNA levels first noted 2 h after HRG treatment. HRG reduced the rate of transcription of ErbB2 and ErbB3 mRNA, but did not affect ErbB2 or ErbB3 mRNA stability. To test if ErbB2 kinase activity was required for the HRG‐induced downregulation, we treated cells with the ErbB2/EGFR inhibitor lapatinib. Lapatinib diminished the HRG‐induced decrease in ErbB2 and ErbB3 mRNA and protein, suggesting that the kinase activity of EGFR/ErbB2 is involved in the HRG‐induced receptor downregulation. Further, HRG‐mediated decreases in ErbB2/3 mRNA transcription are reversed by inhibiting the AKT but not MAPK pathway. To examine the functional consequences of HRG‐mediated decreases in ErbB receptor levels, we performed cell‐cycle analysis. HRG blocked cell‐cycle progression and lapatinib reversed this block. Our findings support a role for HRG in the negative regulation of ErbB expression and suggest that inhibition of ErbB2/3 signaling by ErbB2 directed therapies may interfere with this process. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Combined EGFR and Autophagy Modulation Impairs Cell Migration and Enhances
           Radiosensitivity in Human Glioblastoma Cells
    • Abstract: Glioblastoma (GBM) remains the most aggressive and lethal brain tumor due to its molecular heterogeneity and high motility and invasion capabilities of its cells, resulting in high resistance to current standard treatments (surgery, followed by ionizing radiation combined with Temozolomide chemotherapy administration). Locus amplification, gene overexpression, and genetic mutations of epidermal growth factor receptor (EGFR) are hallmarks of GBM that can ectopically activate downstream signaling oncogenic cascades such as PI3K/Akt/mTOR pathway. Importantly, alteration of this pathway, involved also in the regulation of autophagy process, can improve radioresistance in GBM cells, thus promoting the aggressive phenotype of this tumor. In this work, the endogenous EGFR expression profile and autophagy were modulated to increase radiosensitivity behavior of human T98G and U373MG GBM cells. Our results primarily indicated that EGFR interfering induced radiosensitivity according to a decrease of the clonogenic capability of the investigated cells, and an effective reduction of the in vitro migratory features. Moreover, EGFR interfering resulted in an increase of Temozolomide (TMZ) cytotoxicity in T98G TMZ‐resistant cells. In order to elucidate the involvement of the autophagy process as pro‐death or pro‐survival role in cells subjected to EGFR interfering, the key autophagic gene ATG7 was silenced, thereby producing a transient block of the autophagy process. This autophagy inhibition rescued clonogenic capability of irradiated and EGFR‐silenced T98G cells, suggesting a pro‐death autophagy contribution. To further confirm the functional interplay between EGFR and autophagy pathways, Rapamycin‐mediated autophagy induction during EGFR modulation promoted further impairment of irradiated cells, in terms of clonogenic and migration capabilities. Taken together, these results might suggest a novel combined EGFR‐autophagy modulation strategy, to overcome intrinsic GBM radioresistance, thus improving the efficacy of standard treatments. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Autophagy Is Modulated in Human Neuroblastoma Cells Through Direct
           Exposition to Low Frequency Electromagnetic Fields
    • Abstract: In neurogenerative diseases, comprising Alzheimer's (AD), functional alteration in autophagy is considered one of the pathological hallmarks and a promising therapeutic target. Epidemiological investigations on the possible causes undergoing these diseases have suggested that electromagnetic fields (EMF) exposition can contribute to their etiology. On the other hand, EMF have therapeutic implications in reactivating neuronal functionality. To partly clarify this dualism, the effect of low‐frequency EMF (LF‐EMF) on the modulation of autophagy was investigated in human neuroblastoma SH‐SY5Y cells, which were also subsequently exposed to Aβ peptides, key players in AD. The results primarily point that LF‐EMF induce a significant reduction of microRNA 30a (miR‐30a) expression with a concomitant increase of Beclin1 transcript (BECN1) and its corresponding protein. Furthermore, LF‐EMF counteract the induced miR‐30a up‐regulation in the same cells transfected with miR‐30a mimic precursor molecules and, on the other side, rescue Beclin1 expression after BECN1 siRNA treatment. The expression of autophagy‐related markers (ATG7 and LC3B‐II) as well as the dynamics of autophagosome formation were also visualized after LF‐EMF exposition. Finally, different protocols of repeated LF‐EMF treatments were assayed to contrast the effects of Aβ peptides in vitro administration. Overall, this research demonstrates, for the first time, that specific LF‐EMF treatments can modulate in vitro the expression of a microRNA sequence, which in turn affects autophagy via Beclin1 expression. Taking into account the pivotal role of autophagy in the clearance of protein aggregates within the cells, our results indicate a potential cytoprotective effect exerted by LF‐EMF in neurodegenerative diseases such as AD. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Sox18 preserves the pulmonary endothelial barrier under conditions of
           increased shear stress
    • Abstract: Shear stress secondary to increased pulmonary blood flow (PBF) is elevated in some children born with congenital cardiac abnormalities. However, the majority of these patients do not develop pulmonary edema, despite high levels of permeability inducing factors. Previous studies have suggested that laminar fluid shear stress can enhance pulmonary vascular barrier integrity. However, little is known about the mechanisms by which this occurs. Using microarray analysis, we have previously shown that Sox18, a transcription factor involved in blood vessel development and endothelial barrier integrity, is up‐regulated in an ovine model of congenital heart disease with increased PBF (shunt). By subjecting ovine pulmonary arterial endothelial cells (PAEC) to laminar flow (20 dyn/cm2), we identified an increase in trans‐endothelial resistance (TER) across the PAEC monolayer that correlated with an increase in Sox18 expression. Further, the TER was also enhanced when Sox18 was over‐expressed and attenuated when Sox18 expression was reduced, suggesting that Sox18 maintains the endothelial barrier integrity in response to shear stress. Further, we found that shear stress up‐regulates the cellular tight junction protein, Claudin‐5, in a Sox18 dependent manner, and Claudin‐5 depletion abolished the Sox18 mediated increase in TER in response to shear stress. Finally, utilizing peripheral lung tissue of 4 week old shunt lambs with increased PBF, we found that both Sox18 and Claudin‐5 mRNA and protein levels were elevated. In conclusion, these novel findings suggest that increased laminar flow protects endothelial barrier function via Sox18 dependent up‐regulation of Claudin‐5 expression.
  • Quantifying Mitotic Chromosome Dynamics and Positioning
    • Abstract: The proper organization and segregation of chromosomes during cell division is essential to the preservation of genomic integrity. To understand the mechanisms that spatially control the arrangement and dynamics of mitotic chromosomes requires imaging assays to quantitatively resolve their positions and movements. Here, we will discuss analytical approaches to investigate the position‐dependent control of mitotic chromosomes in cultured cells. These methods can be used to dissect the specific contributions of mitotic proteins to the molecular control of chromosome dynamics. J. Cell. Physiol. 9999: XX–XX, 2014. © 2014 Wiley Periodicals, Inc.
  • Functional Inhibition of Aquaporin‐3 With a Gold‐Based
           Compound Induces Blockage of Cell Proliferation
    • Abstract: AQP3 has been correlated with higher transport of glycerol, increment of ATP content, and larger proliferation capacity. Recently, we described the gold(III) complex Auphen as a very selective and potent inhibitor of AQP3's glycerol permeability (Pgly). Here we evaluated Auphen effect on the proliferation of various mammalian cell lines differing in AQP3 expression level: no expression (PC12), moderate (NIH/3T3) or high (A431) endogenous expression, cells stably expressing AQP3 (PC12‐AQP3), and human HEK293T cells transiently transfected (HEK‐AQP3) for AQP3 expression. Proliferation was evaluated in the absence or presence of Auphen (5 μM) by counting number of viable cells and analyzing 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation. Auphen reduced ≈50% the proliferation in A431 and PC12‐AQP3, ≈15% in HEK‐AQP3 and had no effect in wt‐PC12 and NIH/3T3. Strong arrest in the S‐G2/M phases of the cell cycle, supported by analysis of cyclins (A, B1, D1, E) levels, was observed in AQP3‐expressing cells treated with Auphen. Flow‐cytometry of propidium iodide incorporation and measurements of mitochondrial dehydrogenases activity confirmed absence of cytotoxic effect of the drug. Functional studies evidenced ≈50% inhibition of A431 Pgly by Auphen, showing that the compound's anti‐proliferative effect correlates with its ability to inhibit AQP3 Pgly. Role of Cys‐40 on AQP3 permeability blockage by Auphen was confirmed by analyzing the mutated protein (AQP3‐Ser‐40). Accordingly, cells transfected with mutated AQP3 gained resistance to the antiproliferative effect of Auphen. These results highlight an Auphen inhibitory effect on proliferation of cells expressing AQP3 and suggest a targeted therapeutic effect on carcinomas with large AQP3 expression. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Biological Effects of Insulin and Its Analogs on Cancer Cells With
           Different Insulin Family Receptor Expression
    • Abstract: Hyperinsulinemia is a likely cause of the increased cancer incidence and mortality in diabetic patients, but its role is difficult to define in vivo. Previous in vitro studies testing the mitogenic potential of insulin and its analogs provided incomplete and sometimes contradictory results. To better evaluate cancer cell responsiveness to insulin, to its analogs and to IGF‐I, we measured under identical experimental conditions cell proliferation, invasiveness, and foci formation in six cancer cell lines with different insulin receptor family expression levels. The cancer cells studied have a different expression of insulin receptor (IR), its isoforms (IR‐A and IR‐B), and of the IGF‐I receptor. The data indicate that insulin stimulates proliferation in all cancer cell lines, invasiveness in some, and foci formation in none. Cancer cell responses to insulin (and IGF‐I) are not related to receptor expression levels; moreover, hormone‐stimulated proliferation and invasiveness are not correlated. IGF‐I is a more potent stimulator than insulin in most but not all cancer cell lines. Insulin analogs including M1 and M2 Glargine metabolites stimulate cancer cells similar to insulin. However, exceptions occur for specific analogs in particular cancer cells. In conclusion, in vitro insulin is an effective growth factor for all cancer cells but the biological response to insulin cannot be predicted on the basis of receptor expression levels. In the clinical setting, these observations should be taken in account when deciding treatment for diabetic patients who are at risk of undiscovered cancer or survivors of oncological diseases. J. Cell. Physiol. 9999: XX–XX, 2014. © 2014 Wiley Periodicals, Inc.
  • Probiotic L. reuteri Treatment Prevents Bone Loss in a Menopausal
           Ovariectomized Mouse Model
    • Abstract: Estrogen deficiency is a major risk factor for osteoporosis that is associated with bone inflammation and resorption. Half of women over the age of 50 will experience an osteoporosis related fracture in their lifetime, thus novel therapies are needed to combat post‐menopausal bone loss. Recent studies suggest an important role for gut‐bone signaling pathways and the microbiota in regulating bone health. Given that the bacterium Lactobacillus reuteri ATCC PTA 6475 (L. reuteri) secretes beneficial immunomodulatory factors, we examined if this candidate probiotic could reduce bone loss associated with estrogen deficiency in an ovariectomized (Ovx) mouse menopausal model. Strikingly, L. reuteri treatment significantly protected Ovx mice from bone loss. Osteoclast bone resorption markers and activators (Trap5 and RANKL) as well as osteoclastogenesis are significantly decreased in L. reuteri treated mice. Consistent with this, L. reuteri suppressed Ovx‐induced increases in bone marrow CD4+ T‐lymphocytes (which promote osteoclastogenesis) and directly suppressed osteoclastogenesis in vitro. We also identified that L. reuteri treatment modifies microbial communities in the Ovx mouse gut. Together, our studies demonstrate that L. reuteri treatment suppresses bone resorption and loss associated with estrogen deficiency. Thus, L. reuteri treatment may be a straightforward and cost‐effective approach to reduce post‐menopausal bone loss. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
  • Metabolomics Biomarkers of Frailty in Elderly Breast Cancer Patients
    • Abstract: Metabolome analysis has emerged as a powerful technique for detecting and define specific physio‐pathological phenotypes. In this investigation the diagnostic potential of metabolomics has been applied to better characterize the multiple biochemical alterations that concur in the definition of the frailty phenotype observed in elderly breast cancer patients. The study included 89 women with breast cancer (range 70–97 years) classified as Fit (n = 49), Unfit (n = 23), or Frail (n = 17) according to comprehensive geriatric assessment. The serum metabolomic profile was performed by tandem mass spectrometry and included different classes of metabolites such as amino acids, acylcarnitines, sphingo‐, and glycerol‐phospolipids. ANOVA was applied to identify the metabolites differing significantly among Fit, Unfit, and Frail patients. In patients carrying the frail phenotype, the amino acid perturbations involve serine, tryptophan, hydroxyproline, histidine, its derivate 3‐methyl‐hystidine, cystine, and β‐aminoisobutyric acid. With regard to lipid metabolism, the frailty phenotype was characterized by a decrease of a wide number of glycerol‐ and sphingo‐phospholipid metabolites. These metabolomics biomarkers may give a further insight into the biochemical processes involved in the development of frailty in breast cancer patients. Moreover, they might be useful to refine the comprehensive geriatric assessment model. J. Cell. Physiol. 229: 898–902, 2014. © 2013 Wiley Periodicals, Inc.
  • Overexpression of Calreticulin Contributes to the Development and
           Progression of Pancreatic Cancer
    • Abstract: We studied the clinicopathological significance for Calreticulin (CRT) expression in pancreatic cancer (PC), and its functional relationship with other signaling genes (especially with p53) in regulating the biological behavior of PC cells. IHC, IF, IB, and real‐time PCR were used to detect CRT expression in PC, while transfection and drug intervention were used to investigate the functional relationship of CRT with other signaling genes. IHC showed both CRT and p53 expression was significantly increased in PC, compared to that in paired non‐cancerous pancreatic tissues (P 
  • Journal of Cellular Physiology: Volume 229, Number 7, July 2014
    • Abstract: Cover: Micrograph showing LNCaP cells transfected with miR‐663. See article by Jiao et al. on pages 834–844.
  • Table of Contents: Volume 229, Number 7
  • Editor's Choice
  • Krüppel‐Like Factor 4 Regulates Blood‐Tumor Barrier
           Permeability via ZO‐1, Occludin and Claudin‐5
    • Abstract: Blood‐tumor barrier (BTB) constitutes an efficient organization of tight junctions which significantly reduce permeability for chemotherapy drugs. Krüppel‐like factor 4 (KLF4), a member of the Krüppel‐like family, has been documented in endothelial cells and may serve as an essential regulator of endothelial barrier function. However, our knowledge about the expression and function of KLF4 in the endothelial cells of BTB still remains unclear. In this study, we sought to investigate the role of KLF4 in regulation of BTB function as well as the potential molecular mechanisms. Quantitative RT‐PCR, Western blot, and immunofluorescence assays demonstrated that KLF4 was down‐regulated in the glioma endothelial cells (GECs) which were obtained through endothelial cells co‐cultured with glioma cells. Short hairpin RNA targeting KLF4 impaired the integrity of BTB detected by trans‐endothelial electric resistance assay, and meanwhile reduced the expression of ZO‐1, occludin and claudin‐5, demonstrated by quantitative RT‐PCR, Western blot, and immunofluorescence assays. Depletion of KLF4 increased BTB permeability to small molecules detected by permeability assays. Furthermore, luciferase assays and chromatin immunoprecipitation assays showed that KLF4 up‐regulated the promoter activities and interacted with “CACCC” DNA sequence presented in the promoters of ZO‐1, occludin, and claudin‐5. GATA‐1, GATA‐6, Sp1, and Sp3 factors participated in KLF4 regulation of promoter activities through binding to the promoters of tight junctions related proteins. Collectively, our results indicated that KLF4 is a key transcriptional regulator of BTB function by regulating expressions of tight junction related proteins, which would draw growing attention to KLF4 as a potential target for glioma therapy. J. Cell. Physiol. 229: 916–926, 2014. © 2013 Wiley Periodicals, Inc.
  • MEK1/2 Overactivation Can Promote Growth Arrest by Mediating
           ERK1/2‐Dependent Phosphorylation of p70S6K
    • Abstract: The extracellular signal‐regulated kinase (ERK)1/2 mitogen‐activated protein (MAP) kinase pathway has been involved in the positive and negative regulation of cell proliferation. Upon mitogen stimulation, ERK1/ERK2 activation is necessary for G1‐ to S‐phase progression whereas when hyperactived, this pathway could elicit cell cycle arrest. The mechanisms involved are not fully elucidated but a kinase‐independent function of ERK1/2 has been evidenced in the MAPK‐induced growth arrest. Here, we show that p70S6K, a central regulator of protein biosynthesis, is essential for the cell cycle arrest induced by overactivation of ERK1/2. Indeed, whereas MEK1 silencing inhibits cell cycle progression, we demonstrate that active mutant form of MEK1 or MEK2 triggers a G1 phase arrest by stimulating an activation of p70S6K by ERK1/2 kinases. Silencing of ERK1/2 activity by shRNA efficiently suppresses p70S6K phosphorylation on Thr421/Ser424 and S6 phosphorylation on Ser240/244 as well as p21 expression, but these effects can be partially reversed by the expression of kinase‐dead mutant form of ERK1 or ERK2. In addition, we demonstrate that the kinase p70S6K modulates neither the p21 gene transcription nor the stability of the protein but enhances the translation of the p21 mRNA. In conclusion, our data emphasizes the importance of the translational regulation of p21 by the MEK1/2‐ERK1/2‐p70S6K pathway to negatively control the cell cycle progression. J. Cell. Physiol. 229: 903–915, 2014. © 2013 Wiley Periodicals, Inc.
  • Effect of Mechanical Strain on the Collagen VI Pericellular Matrix in
           Anterior Cruciate Ligament Fibroblasts
    • Abstract: Cell–extracellular matrix interaction plays a major role in maintaining the structural integrity of connective tissues and sensing changes in the biomechanical environment of cells. Collagen VI is a widely expressed non‐fibrillar collagen, which regulates tissues homeostasis. The objective of the present investigation was to extend our understanding of the role of collagen VI in human ACL. This study shows that collagen VI is associated both in vivo and in vitro to the cell membrane of knee ACL fibroblasts, contributing to the constitution of a microfibrillar pericellular matrix. In cultured cells the localization of collagen VI at the cell surface correlated with the expression of NG2 proteoglycan, a major collagen VI receptor. The treatment of ACL fibroblasts with anti‐NG2 antibody abolished the localization of collagen VI indicating that collagen VI pericellular matrix organization in ACL fibroblasts is mainly mediated by NG2 proteoglycan. In vitro mechanical strain injury dramatically reduced the NG2 proteoglycan protein level, impaired the association of collagen VI to the cell surface, and promoted cell cycle withdrawal. Our data suggest that the injury‐induced alteration of specific cell–ECM interactions may lead to a defective fibroblast self‐renewal and contribute to the poor regenerative ability of ACL fibroblasts. J. Cell. Physiol. 229: 878–886, 2014. © 2013 Wiley Periodicals, Inc.
  • The ZnR/GPR39 Interacts With the CaSR to Enhance Signaling in Prostate and
           Salivary Epithelia
    • Abstract: Zinc signaling is mediated by the zinc sensing receptor, ZnR, recently suggested to be the same receptor as G‐protein coupled receptor 39, GPR39. However, it is unknown if GPR39 is mediating Zn2+‐dependent signaling in prostate and salivary tissue where changes in zinc concentrations are frequent and of physiological significance. Here, we show that GPR39 is mediating Zn2+‐dependent Ca2+ responses and is regulating activity of MAP and PI3 pathways in prostate cancer cells, PC3, and ductal salivary gland cells, HSY. We next ask whether ZnR/GPR39 interacts with other GPCR family members. We find that endogenous ZnR/GPR39 activity is regulated by the expression and activity of another cation sensing GPCR, the Ca2+‐sensing receptor (CaSR). Although CaSR is not activated by Zn2+, co‐expression of CaSR and ZnR/GPR39 synergistically enhances Ca2+ responses in PC3 and HSY cells. Silencing of the CaSR using siRNA or a dominant negative construct reduces the Zn2+‐dependent signaling. Importantly, overexpression of GPR39 in HEK293 cells is sufficient to trigger Zn2+‐dependent responses. Nevertheless, application of the CaSR agonist spermine, at concentration below its threshold, enhanced Zn2+‐dependent Ca2+ response. Our results suggest that the CaSR interacts with ZnR/GPR39 and thereby regulates its activity. Finally, we show that in PC3 cells ZnR/GPR39 is required for mediating the Zn2+‐dependent activation of MAPK and PI3K, pathways leading to enhanced cell growth. Importantly, Zn2+‐dependent activation of ZnR/GPR39 also enhances the expression of the Ca2+‐binding protein S100A4 that is linked to invasion of prostate cancer cells. J. Cell. Physiol. 229: 868–877, 2014. © 2013 Wiley Periodicals, Inc.
  • ERK5 Pathway Regulates Transcription Factors Important for Monocytic
           Differentiation of Human Myeloid Leukemia Cells
    • Abstract: Mitogen‐activated protein kinases (MAPKs) are important transducers of external signals for cell growth, survival, and other cellular responses including cell differentiation. Several MAPK cascades are known with the MEK1/2‐ERK1/2, JNK, and p38MAPKs receiving most attention, but the role of MEK5‐ERK5 in intracellular signaling deserves more scrutiny, as this pathway transmits signals that can complement ERK/2 signaling. We hypothesized that the ERK5 pathway plays a role in the control of monocytic differentiation, which is disturbed in myeloid leukemia. We therefore examined the cellular phenotype and key molecular events which occur when human myeloid leukemia cells, acute (AML) or chronic (CML), are forced to differentiate by vitamin D derivatives (VDDs). This study was performed using established cell lines HL60 and U937, and primary cultures of blasts from 10 patients with ML. We found that ERK5 and its direct downstream target transcription factor MEF2C are upregulated by 1,25D in parallel with monocytic differentiation. Further, inhibition of ERK5 activity by specific pharmacological agents BIX02189 and XMD8‐92 alters the phenotype of these cells by reducing the abundance of the VDD‐induced surface monocytic marker CD14, and concomitantly increasing surface expression of the general myeloid marker CD11b. Similar results were obtained when the expression of ERK5 was reduced by siRNA or short hairpin (sh) RNA. ERK5 inhibition resulted in an expected decrease in MEF2C activation. We also found that in AML cells the transcription factor C/EBPβ is positively regulated, while C/EBPα is negatively regulated by ERK5. These findings provide new understanding of dysregulated differentiation in human myeloid leukemia. J. Cell. Physiol. 229: 856–867, 2014. © 2013 Wiley Periodicals, Inc.
  • Acetylsalicylic Acid Inhibits IL‐18‐Induced Cardiac Fibroblast
           Migration Through the Induction of RECK
    • Abstract: The pathogenesis of cardiac fibrosis and adverse remodeling is thought to involve the ROS‐dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs), and the activation and migration of cardiac fibroblasts (CF). Here we investigated the role of RECK (reversion‐inducing‐cysteine‐rich protein with Kazal motifs), a unique membrane‐anchored MMP regulator, on IL‐18‐induced CF migration, and the effect of acetylsalicylic acid (ASA) on this response. In a Matrigel invasion assay, IL‐18‐induced migration of primary mouse CF was dependent on both IKK/NF‐κB‐ and JNK/AP‐1‐mediated MMP9 induction and Sp1‐mediated RECK suppression, mechanisms that required Nox4‐dependent H2O2 generation. Notably, forced expression of RECK attenuated IL‐18‐induced MMP9 activation and CF migration. Further, therapeutic concentrations of ASA inhibited IL‐18‐induced H2O2 generation, MMP9 activation, RECK suppression, and CF migration. The salicylic acid moiety of ASA similarly attenuated IL‐18‐induced CF migration. Thus, ASA may exert potential beneficial effect in cardiac fibrosis through multiple protective mechanisms. J. Cell. Physiol. 229: 845–855, 2014. © 2013 Wiley Periodicals, Inc.
  • Highlights: Volume 229, Number 7
  • Epigenetics and Ocular Diseases: From Basic Biology to Clinical Study
    • Abstract: Epigenetics is an emerging field in ophthalmology and has opened a new avenue for understanding ocular development and ocular diseases related to aging and environment. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and deployment of non‐coding RNAs, result in the heritable silencing of gene expression without any change in DNA sequence. Accumulating evidence suggests a potential link between gene expression, chromatin structure, non‐coding RNAs, and cellular differentiation during ocular development. Disruption of the balance of epigenetic networks could become the etiology of several ocular diseases. Here, we summarized the current knowledge about epigenetic regulatory mechanisms in ocular development and diseases. J. Cell. Physiol. 229: 825–833, 2014. © 2013 Wiley Periodicals, Inc.
  • miR‐663 Induces Castration‐Resistant Prostate Cancer
           Transformation and Predicts Clinical Recurrence
    • Abstract: Castration‐resistant prostate cancer (CRPC) and its treatment are challenging issues in prostate cancer management. Here, we report that miR‐663 is upregulated in CRPC tissues. Overexpression of miR‐663 in prostate LNCaP cells promotes cell proliferation and invasion, neuroendocrine differentiation, and reduction in dihydrotestosterone‐induced upregulation of prostate‐specific antigen expression. Furthermore, results of in situ hybridization show that miR‐663 expression is correlated with Gleason score and TNM stage and is an independent prognostic predictor of clinical recurrence. Together, these findings suggest that miR‐663 is a potential oncomiR for CRPC and may serve as a tumor biomarker for the early diagnosis of CRPC. J. Cell. Physiol. 229: 834–844, 2014. © 2013 Wiley Periodicals, Inc.
  • Regulation of Plasticity and Fibrogenic Activity of Trabecular Meshwork
           Cells by Rho GTPase Signaling
    • Abstract: Glaucoma, a prevalent blinding disease is commonly associated with increased intraocular pressure due to impaired aqueous humor (AH) drainage through the trabecular meshwork (TM). Although increased TM tissue contraction and stiffness in association with accumulation of extracellular matrix (ECM) are believed to be partly responsible for increased resistance to AH outflow, the extracellular cues and intracellular mechanisms regulating TM cell contraction and ECM production are not well defined. This study tested the hypothesis that sustained activation of Rho GTPase signaling induced by lysophosphatidic acid (LPA), TGF‐β, and connective tissue growth factor (CTGF) influences TM cell plasticity and fibrogenic activity which may eventually impact resistance to AH outflow. Various experiments performed using human TM cells revealed that constitutively active RhoA (RhoAV14), TGF‐β2, LPA, and CTGF significantly increase the levels and expression of Fibroblast Specific Protein‐1 (FSP‐1), α‐smooth muscle actin (αSMA), collagen‐1A1 and secretory total collagen, as determined by q‐RT‐PCR, immunofluorescence, immunoblot, flow cytometry and the Sircol assay. Significantly, these changes appear to be mediated by Serum Response Factor (SRF), myocardin‐related transcription factor (MRTF‐A), Slug, and Twist‐1, which are transcriptional regulators known to control cell plasticity, myofibroblast generation/activation and fibrogenic activity. Additionally, the Rho kinase inhibitor‐Y27632 and anti‐fibrotic agent‐pirfenidone were both found to suppress the TGF‐β2‐induced expression of αSMA, FSP‐1, and collagen‐1A1. Taken together, these observations demonstrate the significance of RhoA/Rho kinase signaling in regulation of TM cell plasticity, fibrogenic activity, and myofibroblast activation, events with potential implications for the pathobiology of elevated intraocular pressure in glaucoma patients. J. Cell. Physiol. 229: 927–942, 2014. © 2013 Wiley Periodicals, Inc.
  • BMP‐2 Induction of Dlx3 Expression Is Mediated by p38/Smad5
           Signaling Pathway in Osteoblastic MC3T3‐E1 Cells
    • Abstract: Dlx3 is essential for osteoblast differentiation and bone formation, and its expression is regulated by bone morphogenetic protein‐2 (BMP‐2). However, the intimate mechanism of BMP‐2 regulation of Dlx3 transcription in osteoblasts is still unknown. Considering the important roles of Smad5 and p38 in osteoblast differentiation, we hypothesized that Smad5 and p38 mediated BMP‐2‐induced Dlx3 transcription in osteoblasts. We found activation of Smad5 and p38 increased the expression of Dlx3, whereas knocking down Smad5 or inactivation of p38 inhibited BMP‐2‐induced Dlx3 expression. Both Smad5 and p38 were able to activate Dlx3 promoter activity and p38/Smad5 response elements were located from −698 to −368 in Dlx3 promoter. Two Smad5 binding sites (SBEI and SBEII, TGTCT box) were identified in this region by EMSA and ChIP assay. Deletions and mutagenesis study of the Dlx3 promoter region indicated that the TGTCT boxes are crucial for p38/Smad5‐induced Dlx3 promoter activity. At last, we found a cross‐talk between p38 and Smad5, and that activation of p38 is necessary for BMP‐2‐induced Smad5 phosphorylation and nuclear translocation. Overall, we provide a novel insight that BMP‐2‐induced Dlx3 expression is regulated by p38/Smad5 signaling pathway in osteoblasts. J. Cell. Physiol. 229: 943–954, 2014. © 2013 Wiley Periodicals, Inc.
  • Osteoactivin Induces Transdifferentiation of C2C12 Myoblasts Into
    • Abstract: Osteoactivin (OA) is a novel osteogenic factor important for osteoblast differentiation and function. Previous studies showed that OA stimulates matrix mineralization and transcription of osteoblast specific genes required for differentiation. OA plays a role in wound healing and its expression was shown to increase in post fracture calluses. OA expression was reported in muscle as OA is upregulated in cases of denervation and unloading stress. The regulatory mechanisms of OA in muscle and bone have not yet been determined. In this study, we examined whether OA plays a role in transdifferentiation of C2C12 myoblast into osteoblasts. Infected C2C12 with a retroviral vector overexpressing OA under the CMV promoter were able to transdifferentiate from myoblasts into osteoblasts. Immunofluorescence analysis showed that skeletal muscle marker MF‐20 was severely downregulated in cells overexpressing OA and contained significantly less myotubes compared to uninfected control. C2C12 myoblasts overexpressing OA showed an increase in expression of bone specific markers such as alkaline phosphatase and alizarin red staining, and also showed an increase in Runx2 protein expression. We also detected increased levels of phosphorylated focal adhesion kinase (FAK) in C2C12 myoblasts overexpressing OA compared to control. Taken together, our results suggest that OA is able to induce transdifferentiation of myoblasts into osteoblasts through increasing levels of phosphorylated FAK. J. Cell. Physiol. 229: 955–966, 2014. © 2013 Wiley Periodicals, Inc.
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