Differential regulation of platelet‐derived growth factor stimulated migration and proliferation in osteoblastic cells

Mehrotra, Meenal; Krane, Stephen M.; Walters, Kristen; Pilbeam, Carol C.

doi:10.1002/jcb.20138

Cited by 70 publications

(48 citation statements)

References 52 publications

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“…To the best of our knowledge, our study is the first to report this phenomenon in tumor cells. Our conclusion of involvement of both MAPKs in tumor cell line proliferation is also supported by reports of involvement of ERK and JNK in the proliferation of nontumorous EPOdependent erythroid cells (30), as well as in platelet-derived growth factor-induced proliferation of oesteoblastic MC3T3-E1 cells (46). In summary, our present observation shows that AR42J cells express EPOR.…”

Section: Discussionsupporting

confidence: 91%

Erythropoietin enhancement of rat pancreatic tumor cell proliferation requires the activation of ERK and JNK signals

Bose

Udupa²

2008

American Journal of Physiology-Cell Physiology

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Bose C, Udupa KB. Erythropoietin enhancement of rat pancreatic tumor cell proliferation requires the activation of ERK and JNK signals. Am J Physiol Cell Physiol 295: C394 -C405, 2008. First published June 11, 2008; doi:10.1152/ajpcell.00423.2007 regulates the proliferation and differentiation of erythroid cells by binding to its specific transmembrane receptor EPOR. Recent studies, however, have shown that the EPOR is additionally present in various cancer cells and EPO induces the proliferation of these cells, suggesting a different function for EPO other than erythropoiesis. Therefore, the purpose of the present study was to examine EPOR expression and the role of EPO in the proliferation and signaling cascades involved in this process, using the rat pancreatic tumor cell line AR42J. Our results showed that AR42J cells expressed EPOR, and EPO significantly enhanced their proliferation. Cell cycle analysis of EPO-treated cells indicated an increased percentage of cells in the S phase, whereas cell numbers in G0/G1 phase were significantly reduced. Phosphorylation of extracellular regulatory kinase 1/2 (ERK1/2) and c-Jun NH 2 terminal kinase 1/2 (JNK1/2) was rapidly stimulated and sustained after EPO addition. Treatment of cells with mitogen-activated protein/ERK kinase (MEK) inhibitor PD98059 or JNK inhibitor SP600125 significantly inhibited EPOenhanced proliferation and also increased the fraction of cells in G0/G1 phase. Furthermore, the inhibition of JNK using small interference RNA (siRNA) suppressed EPO-enhanced proliferation of AR42J cells. Taken together, our results indicate that AR42J cells express EPOR and that the activation of both ERK1/2 and JNK1/2 by EPO is essential in regulating proliferation and the cell cycle. Thus both appear to play a key role in EPO-enhanced proliferation and suggest that the presence of both is required for EPO-mediated proliferation of AR42J cells. erythropoietin receptor; cell signaling; mitogen-activated protein kinase induction ERYTHROPOIETIN (EPO) is a glycoprotein hormone that plays a crucial role in erythropoiesis (39,65). Its discovery and preparation through recombinant technology have made it available as a therapeutic drug. Moreover, with pure EPO available, its effect on erythroid cells has been determined to occur via its specific cell surface receptor EPOR (13).

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Section: Discussionsupporting

confidence: 91%

Erythropoietin enhancement of rat pancreatic tumor cell proliferation requires the activation of ERK and JNK signals

Bose

Udupa²

2008

American Journal of Physiology-Cell Physiology

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“…We have noted previously that unlike the case of many other mitogens such as platelet-derived growth factor and fibroblast growth factor-2 (whereby stimulation of DNA synthesis is measurable already after 24 h) (39,40), ϳ48 h are required before the mitogenic action of OGP-(10 -14) becomes traceable (10). We therefore assumed that the OGP-(10 -14)-activated signaling cascade downstream of the MAP kinase involves de novo mRNA and protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

Miguel

Namdar-Attar

Noh

et al. 2005

Journal of Biological Chemistry

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In osteoblasts, the mitogen-activated protein kinases ERK1/2 and p38 as well as the cAMP-response element-binding protein (CREB) have been implicated in the regulation of proliferation and differentiation. The osteogenic growth peptide (OGP) is a 14-mer bone cell mitogen that increases bone formation and trabecular bone density and stimulates fracture healing. OGP-(10 -14) is the physiologically active form of OGP. Using gene array analysis, real-time reverse transcription-PCR, and immunoblot and DNA synthesis assays we show here that in MC3T3 E1 and newborn mouse calvarial osteoblastic cultures the OGP-(10 -14) mitogenic signaling is critically dependent on de novo synthesis of mitogen-activated protein kinase-activated protein kinase 2 (Mapkapk2) mRNA and protein.The increase in Mapkapk2 occurs following short term (5-60 min) stimulation of ERK1/2 activity by OGP-(10 -14); phosphorylation of p38 remains unaffected. Downstream of Mapkapk2, CREB is phosphorylated on Ser 133 leading to its enhanced transcriptional activity. That these events are critical for the OGP-(10 -14) mitogenic signaling is demonstrated by blocking the effects of OGP-(10 -14) on the ERK1/2 pathway, Mapkapk2, CREB, and DNA synthesis using the MEK inhibitor PD098059. The OGP-(10 -14) stimulation of CREB transcriptional activity and DNA synthesis is also blocked by Mapkapk2 siRNA. These data define a novel mitogenic signaling pathway in osteoblasts whereby ERK1/2 stimulation of CREB phosphorylation and transcriptional activity as well as DNA synthesis are critically dependent on de novo Mapkapk2 synthesis.In mammalian cells, the family of mitogen-activated protein (MAP) 3 kinases provides a key link between membrane-bound receptors and changes in the pattern of gene expression. The MAP kinases are activated downstream of many different types of receptors, including tyrosine kinase receptors, cytokine receptors, and serpentine G-protein coupled receptors (1, 2). The MAP kinases consist of four subfamilies: the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase/stress-activated kinase, p38 MAP kinase, and ERK 5. Further downstream, they regulate a multitude of transcription factors that control cell proliferation, survival, and differentiation (3, 4). In osteoblasts, ERK1/2-dependent phosphorylation cascades have been implicated in the regulation of proliferation and RUNX2 activity (5, 6). Activation of p38 has been demonstrated in osteoblasts undergoing differentiation after stimulation with bone morphogenetic protein-2 and epidermal growth factor (7,8).The osteogenic growth peptide (OGP) is a 14-mer bone cell mitogen that increases bone formation and trabecular bone density and stimulates fracture healing when administered to mice and rats (9 -11). Transgenic mice overexpressing OGP have a markedly increased peak bone mass (12). OGP is present in mammalian serum in micromolar concentrations mainly complexed to ␣ 2 -macroglobulin (13). Upon its dissociation from the complex, it is proteolytically activated yieldin...

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“…21,22 In addition, PDGF accelerated cell proliferation via mitogen-activated protein kinase 8. 23 Previous research has shown a connection between v-raf-leukemia viral oncogene 1 and serum response factor in the PDGF pathway, and these genes regulate cell proliferation. 24,25 Microarray analysis showed that the expression level of these PDGF-related genes were lower in miR-29a liver than in NC miRNA liver (Figure 8a).…”

Section: Controlling Liver Fibrosis Through Preventionmentioning

confidence: 99%

MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice

et al. 2016

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Differential regulation of platelet‐derived growth factor stimulated migration and proliferation in osteoblastic cells

Cited by 70 publications

References 52 publications

Erythropoietin enhancement of rat pancreatic tumor cell proliferation requires the activation of ERK and JNK signals

Erythropoietin enhancement of rat pancreatic tumor cell proliferation requires the activation of ERK and JNK signals

ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice

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