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Article ; Online: Glutathione transferase Omega 1 confers protection against azoxymethane-induced colorectal tumour formation.

Tummala, Padmaja / Rooke, Melissa / Dahlstrom, Jane E / Takahashi, Shuhei / Casarotto, Marco G / Fernando, Nilisha / Hughes, Mark M / O'Neill, Luke A J / Board, Philip G

Carcinogenesis

2021 Volume 42, Issue 6, Page(s) 853–863

Abstract: Inflammatory bowel disease (IBD) is characterized by multiple alterations in cytokine expression and is a risk factor for colon cancer. The Omega class glutathione transferase GSTO1-1 regulates the release of the pro-inflammatory cytokines interleukin 1β ...

Abstract	Inflammatory bowel disease (IBD) is characterized by multiple alterations in cytokine expression and is a risk factor for colon cancer. The Omega class glutathione transferase GSTO1-1 regulates the release of the pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) by deglutathionylating NEK7 in the NLRP3 inflammasome. When treated with azoxymethane and dextran sodium sulphate (AOM/DSS) as a model of IBD, Gsto1-/- mice were highly sensitive to colitis and showed a significant increase in the size and number of colon tumours compared with wild-type (WT) mice. Gsto1-/- mice treated with AOM/DSS had significantly lower serum IL-1β and IL-18 levels as well as significantly decreased interferon (IFN)-γ, decreased pSTAT1 and increased pSTAT3 levels in the distal colon compared with similarly treated WT mice. Histologically, AOM/DSS treated Gsto1-/- mice showed increased active chronic inflammation with macrophage infiltration, epithelial dysplasia and invasive adenocarcinoma compared with AOM/DSS treated WT mice. Thus, this study shows that GSTO1-1 regulates IL-1β and IL-18 activation and protects against colorectal cancer formation in the AOM/DSS model of IBD. The data suggest that while GSTO1-1 is a new target for the regulation of the NLRP3 inflammasome-associated cytokines IL-1β and IL-18 by small molecule inhibitors, there is a possibility that anti-inflammatory drugs targeting these cytokines may potentiate colon cancer in some situations.
MeSH term(s)	Animals ; Azoxymethane/toxicity ; Carcinogens/toxicity ; Carrier Proteins/physiology ; Colitis/chemically induced ; Colitis/complications ; Colorectal Neoplasms/etiology ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms/prevention & control ; Dextran Sulfate/toxicity ; Glutathione Transferase/physiology ; Inflammation/etiology ; Inflammation/metabolism ; Inflammation/pathology ; Inflammation/prevention & control ; Interleukin-18/blood ; Interleukin-1beta/blood ; Mice ; Mice, Inbred C57BL ; Mice, Knockout
Chemical Substances	Carcinogens ; Carrier Proteins ; Gsto1 protein, mouse ; IL1B protein, mouse ; Interleukin-18 ; Interleukin-1beta ; Dextran Sulfate (9042-14-2) ; Glutathione Transferase (EC 2.5.1.18) ; Azoxymethane (MO0N1J0SEN)
Language	English
Publishing date	2021-02-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603134-1
ISSN	1460-2180 ; 0143-3334
ISSN (online)	1460-2180
ISSN	0143-3334
DOI	10.1093/carcin/bgab008
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Article ; Online: Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors.

Xie, Yiyue / Tummala, Padmaja / Oakley, Aaron J / Deora, Girdhar Singh / Nakano, Yuji / Rooke, Melissa / Cuellar, Matthew E / Strasser, Jessica M / Dahlin, Jayme L / Walters, Michael A / Casarotto, Marco G / Board, Philip G / Baell, Jonathan B

Journal of medicinal chemistry

2020 Volume 63, Issue 6, Page(s) 2894–2914

Abstract: Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent ... ...

Abstract	Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor
MeSH term(s)	Animals ; Drug Development ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Glutathione Transferase/antagonists & inhibitors ; Glutathione Transferase/chemistry ; Glutathione Transferase/metabolism ; Humans ; Male ; Mice ; Molecular Docking Simulation ; Structure-Activity Relationship ; Sulfonamides/chemistry ; Sulfonamides/pharmacology ; Benzenesulfonamides
Chemical Substances	Enzyme Inhibitors ; Sulfonamides ; GSTO1 protein, human (EC 2.5.1.18) ; Glutathione Transferase (EC 2.5.1.18)
Language	English
Publishing date	2020-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.9b01391
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Article: The Role of Primary Cilia in Mesenchymal Stem Cell Differentiation: A Pivotal Switch in Guiding Lineage Commitment.

Tummala, Padmaja / Arnsdorf, Emily J / Jacobs, Christopher R

Cellular and molecular bioengineering

2010 Volume 3, Issue 3, Page(s) 207–212

Abstract: Primary cilia are sensory organelles that have been shown to play a critical role in lineage commitment. It was our hypothesis that the primary cilium is necessary for chemically induced differentiation of human mesenchymal stem cells (MSC). To ... ...

Abstract	Primary cilia are sensory organelles that have been shown to play a critical role in lineage commitment. It was our hypothesis that the primary cilium is necessary for chemically induced differentiation of human mesenchymal stem cells (MSC). To investigate this, polaris siRNA was used to inhibit the primary cilia and the mRNA levels of transcription factors Runx2, PPARgamma were measured by RT PCR as markers of osteogenic, adipogenic and chondrogenic differentiation, respectively. MSCs with inhibited primary cilia had significantly decreased basal mRNA expression levels of all three lineages specific transcription factors indicating that primary cilia are critical in multiple differentiation pathways. Furthermore, to determine if primary cilia play a role in the differentiation potential of MSCs, progenitor cells transfected with either scrambled or polaris siRNA were cultured in osteo-inductive, chondro-inductive, or adipo-inductive media and lineage commitment was ascertained. Interestingly, within 24 h of culture, cells transfected with polaris siRNA in both osteogenic and adipogenic media lost adhesion and released from the slides; however MSCs in chondrogenic media as well as cells transfected with scrambled siRNA did not. These results suggest that the primary cilium is necessary for the normal progression of chemically induced osteogenic and adipogenic differentiation. As a control, the experiment was repeated with NIH3T3 fibroblasts and none of the effects of inhibited primary cilia were observed indicating that the loss of adhesion may be specific to MSCs. Furthermore after biochemically inducing the cells to differentiate, polaris knockdown resulted in abrogation of both Runx2 and PPARgamma mRNA while SOX9 mRNA expression was significantly lower. These results suggest that primary cilia play an essential role not only in the initiation of both osteogenic and adipogenic differentiation, but also in maintaining the phenotype of differentiated cells. Interestingly, chondrogenic differentiation appeared less dependent on a functional primary cilium.
Language	English
Publishing date	2010-08-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2416037-4
ISSN	1865-5033 ; 1865-5025
ISSN (online)	1865-5033
ISSN	1865-5025
DOI	10.1007/s12195-010-0127-x
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Article ; Online: Non-canonical Wnt signaling and N-cadherin related beta-catenin signaling play a role in mechanically induced osteogenic cell fate.

Arnsdorf, Emily J / Tummala, Padmaja / Jacobs, Christopher R

PloS one

2009 Volume 4, Issue 4, Page(s) e5388

Abstract: Background: Understanding how the mechanical microenvironment influences cell fate, and more importantly, by what molecular mechanisms, will enhance not only the knowledge of mesenchymal stem cell biology but also the field of regenerative medicine. ... ...

Abstract	Background: Understanding how the mechanical microenvironment influences cell fate, and more importantly, by what molecular mechanisms, will enhance not only the knowledge of mesenchymal stem cell biology but also the field of regenerative medicine. Mechanical stimuli, specifically loading induced oscillatory fluid flow, plays a vital role in promoting healthy bone development, homeostasis and morphology. Recent studies suggest that such loading induced fluid flow has the potential to regulate osteogenic differentiation via the upregulation of multiple osteogenic genes; however, the molecular mechanisms involved in the transduction of a physical signal into altered cell fate have yet to be determined. Methods and principal findings: Using immuno-staining, western blot analysis and luciferase assays, we demonstrate the oscillatory fluid flow regulates beta-catenin nuclear translocation and gene transcription. Additionally, real time RT-PCR analysis suggests that flow induces Wnt5a and Ror2 upregulation, both of which are essential for activating the small GTPase, RhoA, upon flow exposure. Furthermore, although beta-catenin phosphorylation is not altered by flow, its association with N-cadherin is, indicating that flow-induced beta-catenin signaling is initiated by adherens junction signaling. Conclusion: We propose that the mechanical microenvironment of bone has the potential to regulate osteogenic differentiation by initiating multiple key molecular pathways that are essential for such lineage commitment. Specifically, non-canonical Wnt5a signaling involving Ror2 and RhoA as well as N-cadherin mediated beta-catenin signaling are necessary for mechanically induced osteogenic differentiation.
MeSH term(s)	Adherens Junctions/metabolism ; Animals ; Base Sequence ; Biomechanical Phenomena ; Cadherins/metabolism ; Cell Differentiation ; Cell Line ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Mice ; Models, Biological ; Osteogenesis/physiology ; RNA, Small Interfering/genetics ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptor Tyrosine Kinase-like Orphan Receptors ; Signal Transduction ; Stress, Mechanical ; Wnt Proteins/antagonists & inhibitors ; Wnt Proteins/genetics ; Wnt Proteins/metabolism ; Wnt-5a Protein ; beta Catenin/metabolism ; rho GTP-Binding Proteins/metabolism ; rhoA GTP-Binding Protein
Chemical Substances	CTNNB1 protein, mouse ; Cadherins ; Cdh2 protein, mouse ; RNA, Small Interfering ; Wnt Proteins ; Wnt-5a Protein ; Wnt5a protein, mouse ; beta Catenin ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Receptor Tyrosine Kinase-like Orphan Receptors (EC 2.7.10.1) ; Ror2 protein, mouse (EC 2.7.10.1) ; RhoA protein, mouse (EC 3.6.5.2) ; rho GTP-Binding Proteins (EC 3.6.5.2) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2009-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0005388
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Article: Helicobacter pylori induces somatic mutations in TP53 via overexpression of CHAC1 in infected gastric epithelial cells

Wada, Yuriko / Takemura, Kosuke / Tummala, Padmaja / Uchida, Keisuke / Kitagaki, Keisuke / Furukawa, Asuka / Ishige, Yuuki / Ito, Takashi / Hara, Yukichi / Suzuki, Takashige / Mimuro, Hitomi / Board, Philip G. / Eishi, Yoshinobu

FEBS Open Bio. 2018 Apr., v. 8, no. 4

2018

Abstract: Infection with Helicobacter pylori is known to decrease the level of glutathione in gastric epithelial cells and increase the production of reactive oxygen species (ROS), which can lead to DNA damage and the development of gastric cancer. Cation ... ...

Abstract	Infection with Helicobacter pylori is known to decrease the level of glutathione in gastric epithelial cells and increase the production of reactive oxygen species (ROS), which can lead to DNA damage and the development of gastric cancer. Cation transport regulator 1 (CHAC1) has γ‐glutamylcyclotransferase activity that degrades glutathione. We found that cagA‐positive H. pylori infection triggered CHAC1 overexpression in human gastric epithelial (AGS) cells leading to glutathione degradation and the accumulation of ROS. Nucleotide alterations in the TP53 tumour suppressor gene were induced in AGS cells overexpressing CHAC1, whereas no mutations were detected in cells overexpressing a catalytically inactive mutant of CHAC1. A high frequency of TP53 mutations occurred in H. pylori‐infected AGS cells, but this was prevented in cells transfected with CHAC1 siRNA. These findings indicate that H. pylori‐mediated CHAC1 overexpression degrades intracellular glutathione, allowing the accumulation of ROS which subsequently causes mutations that could contribute to the development of gastric cancer.
Keywords	DNA damage ; Helicobacter pylori ; cations ; epithelium ; glutathione ; humans ; mutants ; reactive oxygen species ; stomach neoplasms ; tumor suppressor genes
Language	English
Dates of publication	2018-04
Size	p. 671-679.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	2651702-4
ISSN	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.12402
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Article ; Online: Beta1 integrins mediate mechanosensitive signaling pathways in osteocytes.

Litzenberger, Julie B / Kim, Jae-Beom / Tummala, Padmaja / Jacobs, Christopher R

Calcified tissue international

2010 Volume 86, Issue 4, Page(s) 325–332

Abstract: Integrins are cell-substrate adhesion proteins that initiate intracellular signaling and may serve as mechanosensors in bone. MLO-Y4 cells were stably transfected with a dominant negative form of the beta(1) integrin subunit (beta(1)DN) containing the ... ...

Abstract	Integrins are cell-substrate adhesion proteins that initiate intracellular signaling and may serve as mechanosensors in bone. MLO-Y4 cells were stably transfected with a dominant negative form of the beta(1) integrin subunit (beta(1)DN) containing the transmembrane domain and cytoplasmic tail of beta(1) integrin. Cells expressing beta(1)DN had reduced vinculin localization to focal contacts but no change in intracellular actin organization. When exposed to oscillatory fluid flow, beta(1)DN cells exhibited a significant reduction in the upregulation of cyclooxygenase-2 gene expression and prostaglandin E(2) release. Similarly, the ratio of receptor activator of NF-kappaB ligand mRNA to osteoprotegerin mRNA decreased significantly after exposure to fluid flow in control cells but not in beta(1)DN cells. Interfering with integrin signaling did not affect mechanically induced intracellular calcium mobilization. These data suggest that integrins may initiate the cellular response of osteocytes to dynamic fluid flow and may serve as mechanosensitive molecules in bone.
MeSH term(s)	Biomechanical Phenomena ; Calcium/metabolism ; Cell Adhesion/genetics ; Cells, Cultured ; Humans ; Integrin beta1/genetics ; Integrin beta1/metabolism ; Integrin beta1/physiology ; Mechanotransduction, Cellular/genetics ; Models, Biological ; Osteocytes/metabolism ; Osteocytes/physiology ; Peptide Fragments/genetics ; Peptide Fragments/metabolism ; Physical Stimulation ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Pulsatile Flow/physiology ; Signal Transduction/genetics ; Transfection
Chemical Substances	Integrin beta1 ; Peptide Fragments ; Protein Subunits ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2010-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	304266-2
ISSN	1432-0827 ; 0944-0747 ; 0008-0594 ; 0171-967X
ISSN (online)	1432-0827
ISSN	0944-0747 ; 0008-0594 ; 0171-967X
DOI	10.1007/s00223-010-9343-6
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Article: Helicobacter pylori

FEBS open bio

2018 Volume 8, Issue 4, Page(s) 671–679

Abstract: Infection ... ...

Abstract	Infection with
Language	English
Publishing date	2018
Publishing country	England
Document type	Journal Article
ISSN	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.12402
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Article ; Online: Glutathione transferase M2 variants inhibit ryanodine receptor function in adult mouse cardiomyocytes.

Samarasinghe, Kaveenda / Liu, Dan / Tummala, Padmaja / Cappello, Jean / Pace, Suzy M / Arnolda, Leonard / Casarotto, Marco G / Dulhunty, Angela F / Board, Philip G

Biochemical pharmacology

2015 Volume 97, Issue 3, Page(s) 269–280

Abstract: Release of Ca(2+) from the sarcoplasmic reticulum (SR) through the cardiac ryanodine receptor (RyR2) is an essential step in cardiac excitation-contraction coupling. Excess Ca(2+) release due to overactive RyR2 can cause arrhythmia that can lead to ... ...

Abstract	Release of Ca(2+) from the sarcoplasmic reticulum (SR) through the cardiac ryanodine receptor (RyR2) is an essential step in cardiac excitation-contraction coupling. Excess Ca(2+) release due to overactive RyR2 can cause arrhythmia that can lead to cardiac arrest. Fragments derived from the carboxy-terminal domain of human glutathione transferase M2 (GSTM2C) specifically inhibit RyR2 activity. Our aim was to further improve this inhibition by mutagenesis and to assess the therapeutic potential of GSTM2C based peptides to treat Ca(2+) release-based arrhythmia. We generated several mutant variants of the C-terminal fragment GSTM2C H5-8 and from those mutant proteins we identified two (RM13 and SM2) that exhibited significantly greater inhibition of cardiac SR Ca(2+) release and single RyR2 channel activity. Flow cytometry analysis showed that these two mutant proteins as well as GSTM2C H5-8 are taken up by isolated adult mouse cardiomyocytes without the aid of any additional compounds, Ca(2+) imaging and isolated cell contraction measurements revealed that GSTM2C H5-8, SM2 and RM13 reduce the SR Ca(2+) release rate and the fractional shortening of adult mouse cardiomyocytes, while importantly increasing the rate of Ca(2+) removal from the sarcoplasm. These observations indicate that peptides derived from GSTM2C inhibit RyR2 at a cellular level and thus they may provide the basis for a novel therapeutic agent to treat arrhythmia and heart attack.
MeSH term(s)	Animals ; Caffeine/pharmacology ; Calcium Channel Blockers/pharmacology ; Cells, Cultured ; Circular Dichroism ; Escherichia coli/genetics ; Glutathione Transferase/genetics ; Male ; Mice, Inbred C57BL ; Mutagenesis, Site-Directed ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Peptide Fragments/genetics ; Peptide Fragments/pharmacology ; Ryanodine Receptor Calcium Release Channel/metabolism ; Two-Hybrid System Techniques
Chemical Substances	Calcium Channel Blockers ; Peptide Fragments ; Ryanodine Receptor Calcium Release Channel ; ryanodine receptor 2. mouse ; Caffeine (3G6A5W338E) ; Glutathione Transferase (EC 2.5.1.18) ; glutathione S-transferase Mu 2 (EC 2.5.1.18)
Language	English
Publishing date	2015-10-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2015.08.004
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Article ; Online: Dichloroacetic acid up-regulates hepatic glutathione synthesis via the induction of glutamate-cysteine ligase.

Theodoratos, Angelo / Blackburn, Anneke C / Cappello, Jean / Tummala, Padmaja / Dahlstrom, Jane E / Board, Philip G

Biochemical pharmacology

2012 Volume 83, Issue 3, Page(s) 427–433

Abstract: Dichloroacetic acid (DCA) has potential for use in cancer therapy and the treatment of metabolic acidosis. However, DCA can create a deficiency of glutathione transferase Zeta (GSTZ1-1). Gstz1 knockout mice have elevated oxidative stress and low ... ...

Abstract	Dichloroacetic acid (DCA) has potential for use in cancer therapy and the treatment of metabolic acidosis. However, DCA can create a deficiency of glutathione transferase Zeta (GSTZ1-1). Gstz1 knockout mice have elevated oxidative stress and low glutathione levels that increases their sensitivity to acetaminophen toxicity. As it is highly likely that patients that are treated with DCA will develop drug induced GSTZ1-1 deficiency we considered they could be at risk of elevated toxicity if they are exposed to other drugs that cause oxidative stress or consume glutathione (GSH). To test this hypothesis we treated mice with DCA and acetaminophen (APAP). Surprisingly, the mice pre-treated with DCA suffered less APAP-mediated hepatotoxicity than untreated mice. This protection is most likely due to an increased capacity for the liver to synthesize GSH, since DCA increased the expression and activity of glutamate-cysteine ligase GCL, the rate-limiting enzyme of GSH synthesis. Other pathways for acetaminophen disposal were unchanged or diminished by DCA. Pre-treatment with DCA may be of use in other settings where the maintenance of protective levels of GSH are required. However, DCA may lower the efficacy of drugs that rely on oxidative stress and the depletion of GSH to enhance their cytotoxicity or of drugs that are detoxified by GSH conjugation. Consequently, as the use of DCA in the clinic is likely to increase, it will be critical to evaluate the interactions of DCA with other drugs to ensure the combinations retain their efficacy and do not cause enhanced toxicity.
MeSH term(s)	Animals ; Dichloroacetic Acid/pharmacology ; Enzyme Induction/drug effects ; Enzyme Induction/genetics ; Glutamate-Cysteine Ligase/biosynthesis ; Glutamate-Cysteine Ligase/deficiency ; Glutamate-Cysteine Ligase/genetics ; Glutathione/biosynthesis ; Liver/drug effects ; Liver/enzymology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Up-Regulation/genetics ; Up-Regulation/physiology
Chemical Substances	Dichloroacetic Acid (9LSH52S3LQ) ; Glutamate-Cysteine Ligase (EC 6.3.2.2) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2012-02-01
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2011.11.012
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Article: Mechanically induced osteogenic differentiation--the role of RhoA, ROCKII and cytoskeletal dynamics.

Arnsdorf, Emily J / Tummala, Padmaja / Kwon, Ronald Y / Jacobs, Christopher R

Journal of cell science

2009 Volume 122, Issue Pt 4, Page(s) 546–553

Abstract: Many biochemical factors regulating progenitor cell differentiation have been examined in detail; however, the role of the local mechanical environment on stem cell fate has only recently been investigated. In this study, we examined whether oscillatory ... ...

Abstract	Many biochemical factors regulating progenitor cell differentiation have been examined in detail; however, the role of the local mechanical environment on stem cell fate has only recently been investigated. In this study, we examined whether oscillatory fluid flow, an exogenous mechanical signal within bone, regulates osteogenic, adipogenic or chondrogenic differentiation of C3H10T1/2 murine mesenchymal stem cells by measuring Runx2, PPARgamma and SOX9 gene expression, respectively. Furthermore, we hypothesized that the small GTPase RhoA and isometric tension within the actin cytoskeleton are essential in flow-induced differentiation. We found that oscillatory fluid flow induces the upregulation of Runx2, Sox9 and PPARgamma, indicating that it has the potential to regulate transcription factors involved in multiple unique lineage pathways. Furthermore, we demonstrate that the small GTPase RhoA and its effector protein ROCKII regulate fluid-flow-induced osteogenic differentiation. Additionally, activated RhoA and fluid flow have an additive effect on Runx2 expression. Finally, we show RhoA activation and actin tension are negative regulators of both adipogenic and chondrogenic differentiation. However, an intact, dynamic actin cytoskeleton under tension is necessary for flow-induced gene expression.
MeSH term(s)	Actins/metabolism ; Adipogenesis ; Animals ; Cell Differentiation ; Cell Line ; Chondrogenesis ; Core Binding Factor Alpha 1 Subunit/biosynthesis ; Core Binding Factor Alpha 1 Subunit/genetics ; Cytoskeleton/chemistry ; Cytoskeleton/enzymology ; Enzyme Induction ; Extracellular Fluid ; Gene Expression Regulation, Developmental ; Mesenchymal Stem Cells/cytology ; Mice ; Osteogenesis ; PPAR gamma/biosynthesis ; PPAR gamma/genetics ; SOX9 Transcription Factor/biosynthesis ; SOX9 Transcription Factor/genetics ; Stress, Mechanical ; Up-Regulation ; rho GTP-Binding Proteins/biosynthesis ; rho-Associated Kinases/biosynthesis ; rhoA GTP-Binding Protein
Chemical Substances	Actins ; Core Binding Factor Alpha 1 Subunit ; PPAR gamma ; Runx2 protein, mouse ; SOX9 Transcription Factor ; Sox9 protein, mouse ; Rock2 protein, mouse (EC 2.7.11.1) ; rho-Associated Kinases (EC 2.7.11.1) ; RhoA protein, mouse (EC 3.6.5.2) ; rho GTP-Binding Proteins (EC 3.6.5.2) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2009-01-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.036293
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