p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation

Halawani, Dalia; Mondeh, Rhoda; Stanton, Lee‐Anne; Beier, Frank

doi:10.1038/sj.onc.1207422

Cited by 48 publications

(42 citation statements)

References 38 publications

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“…Immunoprecipitated (IP) Cdk2 activity was measured in a kinase assay using histone H1 as a substrate and [g- airway smooth muscle cells stimulated by fibroblast growth factor-2 (22, 23), of hematopoietic cells stimulated by cytokines (24,25), and of vascular smooth muscle and pancreatic stellate cells stimulated by platelet-derived growth factor (26,27). p38 MAPKs are also required for CD40-induced proliferation of B-lymphocytes (28), and for cell cycle progression of breast cancer, melanoma and chondrosarcoma cell lines (29)(30)(31). However, the signaling pathways and identities of signaling key intermediates, which mediate p38 MAPK involvement in cell cycle progression, are poorly characterized.…”

Section: Discussionmentioning

confidence: 99%

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

Correze¹,

Blondeau²,

Pomérance³

2005

eur j endocrinol

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Objective: Thyrotropin activates the cAMP pathway in thyroid cells, and stimulates cell cycle progression in cooperation with insulin or insulin-like growth factor-I. Because p38 mitogen-activated protein kinases (p38 MAPKs) were stimulated by cAMP in the FRTL-5 rat thyroid cell line, we investigated (i) the effect of the specific inhibition of p38 MAPKs on FRTL-5 cell proliferation and (ii) the mechanism of action of p38 MAPKs on cell cycle control, by studying the expression and/or the activity of several cell cycle regulatory proteins in FRTL-5 cells. Methods: DNA synthesis was monitored by incorporation of [ 3 H]thymidine into DNA and the cell cycle distribution was assessed by fluorescence-activated cell sorter analysis. Expression of cell cycle regulatory proteins was determined by Western blot analysis. Cyclin-dependent kinase 2 (Cdk2) activity associated to cyclin E was immunoprecipitated and was measured by an in vitro kinase assay. Results: SB203580, an inhibitor of a and b isoforms of p38 MAPKs, but not its inactive analog SB202474, inhibited DNA synthesis and the G1-S transition induced by forskolin plus insulin. SB203580 inhibited specifically p38 MAPK activity but not other kinase activities such as Akt and p70-S6 kinase. Treatment of FRTL-5 cells with SB203580 decreased total and cyclin E-associated Cdk2 kinase activity stimulated with forskolin and insulin. However, inhibition of p38 MAPKs by SB203580 was without effect on total cyclin E and Cdk2 levels. The decrease in Cdk2 kinase activity caused by SB203580 treatment was not due to an increased expression of p21Cip1 or p27 Kip1 inhibitory proteins. In addition, SB203580 affected neither Cdc25A phosphatase expression nor Cdk2 Tyr-15 phosphorylation. Inhibition of p38 MAPKs decreased Cdk2-cyclin E activation by regulating the subcellular localization of Cdk2 and its phosphorylation on Thr-160. Conclusions: These results indicate that p38 MAPK activity is involved in the regulation of cell cycle progression in FRTL-5 thyroid cells, at least in part by increasing nuclear Cdk2 activity. 153 123-133 European Journal of Endocrinology

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Section: Discussionmentioning

confidence: 99%

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

Correze¹,

Blondeau²,

Pomérance³

2005

eur j endocrinol

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“…20 l of lysate were used to determine relative luciferase activity (firefly luciferase activity divided by Renilla luciferase activity) using a dual luciferase assay system (Promega). Data analyses were done as described previously (47).…”

Section: Methodsmentioning

confidence: 99%

RhoA/ROCK Signaling Regulates Sox9 Expression and Actin Organization during Chondrogenesis

Woods¹,

Wang²,

Beier

2005

Journal of Biological Chemistry

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269

277

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Endochondral ossification is initiated by the differentiation of mesenchymal precursor cells to chondrocytes (chondrogenesis). This process is characterized by a strong interdependence of cell shape, cytoskeletal organization, and the onset of chondrogenic gene expression, but the molecular mechanisms mediating these interactions are not known. Here we investigated the role of the RhoA/ROCK pathway, a well characterized regulator of cytoskeletal organization, in chondrogenesis. We show that pharmacological inhibition of ROCK signaling by Y27632 resulted in increased glycosaminoglycan synthesis and elevated expression of the chondrogenic transcription factor Sox9, whereas overexpression of RhoA in the chondrogenic cell line ATDC5 had the opposite effects. Suppression of Sox9 expression by ROCK signaling was achieved through repression of Sox9 promoter activity. These molecular changes were accompanied by reorganization of the actin cytoskeleton, where RhoA/ROCK signaling suppressed cortical actin organization, a hallmark of differentiated chondrocytes. This led us to analyze the regulation of Sox9 expression by drugs affecting cytoskeletal dynamics. Both inhibition of actin polymerization by cytochalasin D and stabilization of existing actin filaments by jasplakinolide resulted in increased Sox9 mRNA levels, whereas inhibition of microtubule polymerization by colchicine completely blocked Sox9 expression. In conclusion, our data suggest that RhoA/ROCK signaling suppresses chondrogenesis through the control of Sox9 expression and actin organization.

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“…A number of in vitro studies have suggested that p38 potentially regulates chondrocyte proliferation. However, both proliferative and antiproliferative effects have been reported based on the effects of p38 inhibitors in a number of culture systems (18,21,25,26). Therefore, examining how increased or decreased p38 activity in chondrocytes affects chondrocyte differentiation, proliferation, and the entire process of endochondral ossification in intact animals is of considerable interest.…”

mentioning

confidence: 99%

“…Indeed, we recently showed that constitutive activation of the MEK1-MAPK pathway in chondrocytes in transgenic mice inhibits hypertrophic chondrocyte differentiation and causes a dwarf phenotype without a decrease in cell proliferation (16). The p38 MAPK pathway, another subfamily of the MAPK pathways, has also been shown to affect chondrocyte differentiation in chondrocyte cultures (17)(18)(19)(20)(21)(22)(23). p38 MAPKs consist of four isoforms, all of which are activated by MKK6, an upstream MAPKK (24).…”

mentioning

confidence: 99%

Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation

Zhang

Murakami

Coustry

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Accumulating in vitro evidence suggests that the p38 mitogenactivated protein kinase (MAPK) pathway is involved in endochondral ossification. To investigate the role of this pathway in endochondral ossification, we generated transgenic mice with expression in chondrocytes of a constitutively active mutant of MKK6, a MAPK kinase that specifically activates p38. These mice had a dwarf phenotype characterized by reduced chondrocyte proliferation, inhibition of hypertrophic chondrocyte differentiation, and a delay in the formation of primary and secondary ossification centers. Histological analysis with in situ hybridization showed reduced expression of Indian hedgehog, PTH͞PTH-related peptide receptor (PTH, parathyroid hormone), cyclin D1, and increased expression of p21 in chondrocytes. In addition, both in vivo and in transfected cells, p38 signaling increased the transcriptional activity of Sox9, a transcription factor essential for chondrocyte differentiation. In agreement with this observation, transgenic mice that express a constitutively active mutant of MKK6 in chondrocytes showed phenotypes similar to those of mice that overexpress SOX9 in chondrocytes. These observations are consistent with the notion that increased activity of Sox9 accounts at least in part for the phenotype caused by constitutive activation of MKK6 in chondrocytes. Therefore, our study provides in vivo evidence for the role of p38 in endochondral ossification and suggests that Sox9 is a likely downstream target of the p38 MAPK pathway.E ndochondral ossification, a process involving a cartilage intermediate, is responsible for the formation of most vertebrate skeletal elements. After the condensation of mesenchymal chondroprogenitor cells (1), cells differentiate into chondrocytes, which express cartilaginous matrix molecules and form cartilage that prefigures future skeletal elements. Endochondral bone growth takes place at the growth plate, where chondrocytes undergo unidirectional proliferation and then become hypertrophic chondrocytes. Hypertrophic chondrocytes eventually undergo apoptosis and are replaced by bone cells (2). This complex process of endochondral ossification is under the concerted regulation of various cytokines and growth factors, including fibroblast growth factors (FGFs), parathyroid hormone (PTH)-related peptide, Indian hedgehog (Ihh), and bone morphogenetic proteins (3-7).Several transcription factors, including Sox9, Sox5, Sox6, Osterix, and Runx2, have critical roles in endochondral ossification (8-12). In particular, we previously showed that Sox9 has an essential role at sequential steps in the chondrocyte differentiation pathway (8, 9). Indeed, Sox9 is needed for the condensation of chondrogenic mesenchymal cells; it is also required for the overt differentiation of these cells into chondrocytes, in part because Sox9 is needed for the expression of Sox5 and Sox6, which are also needed at this step. A further role for Sox9 is inhibition of the proliferation of chondrocytes and of the transition of these cells...

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p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation

Cited by 48 publications

References 38 publications

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

RhoA/ROCK Signaling Regulates Sox9 Expression and Actin Organization during Chondrogenesis

Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation

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