Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA

Charron, Frédéric; Tsimiklis, George; Arcand, Mathieu; Robitaille, Lucie; Liang, Qiangrong; Molkentin, Jeffery D.; Meloche, Sylvain; Nemer, Mona

doi:10.1101/gad.915701

Cited by 204 publications

(228 citation statements)

References 84 publications

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“…This phosphorylation is a prerequisite for Mef2c translocation to the nucleus [47]. (b) Similarly, Gata4 phosphorylation by p38 MAPK increases its DNA-binding in the stress-induced adult heart [49], and greatly increases Gata4 transcriptional activity during sarcomeric organization [50]. The fact that Gata4 and also Mef2c were mislocalized to the cytosolic compartment under low glucose conditions suggests this possibility.…”

Section: Discussionmentioning

confidence: 97%

Mitochondrial Reactive Oxygen Species Mediate Cardiomyocyte Formation from Embryonic Stem Cells in High Glucose

et al. 2010

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Accumulating evidence points to reactive oxygen species (ROS) as important signaling molecules for cardiomyocyte differentiation in embryonic stem (ES) cells. Given that ES cells are normally maintained and differentiated in medium containing supraphysiological levels of glucose (25 mM), a condition which is known to result in enhanced cellular ROS formation, we questioned whether this high glucose concentration was necessary for cardiomyocyte lineage potential. We show here that ES cells cultured in physiological glucose (5 mM), maintained their general stemness qualities but displayed an altered mitochondrial metabolism, which resulted in decreased ROS production. Furthermore, ES and induced pluripotent stem (iPS) cells differentiated in lower glucose concentrations failed to generate cardiomyocyte structures; an effect mimicked with antioxidant treatments using catalase, N-acetyl cysteine and mitoubiquinone, under high glucose conditions in ES cells. Molecular analysis revealed that ES cells differentiated in 5 mM glucose had reduced expression of the pro-cardiac NOX4 gene and diminished phosphorylation of p38 mitogen-activated protein kinase (MAPK), together with specific changes in the cardiac transcriptional network. These outcomes could be reversed by supplementation of low glucose cultures with ascorbic acid, paradoxically acting as a pro-oxidant. Furthermore, forced expression of an upstream p38 MAPK kinase (MKK6) could bypass the requirement for ROS during differentiation to cardiomyocytes under low glucose conditions, illustrating a key role for p38 in the cardiac differentiation program. Together these data demonstrate that endogenous ROS control is important for cardiomyocyte formation from ES cells, and furthermore that supraphysiological glucose, by supplying ROS, is absolutely required.

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Section: Discussionmentioning

confidence: 97%

Mitochondrial Reactive Oxygen Species Mediate Cardiomyocyte Formation from Embryonic Stem Cells in High Glucose

et al. 2010

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“…AT1R may activate STAT proteins via JAK2-dependent or -independent pathways (16,63). On the other hand, contribution of the GATA element in the AII response may be the result of activation of the MAPK cascade, which could lead to phosphorylation and potentiation of GATA-4 activity as reported previously (15,41). To test the involvement of the various signaling cascades in AII regulation of transcription, we first checked the effects of various pharmacologic inhibitors on the ANF promoter response to AII.…”

Section: Resultsmentioning

confidence: 99%

“…GATA-4, a member of the GATA family of tissue-specific zinc finger proteins, is a critical regulator of cardiogenesis (26,58). In postnatal cardiomyocytes, GATA-4 is essential for maintaining the cardiac genetic program (14) and for the adaptive response of the heart to numerous stimuli, including hormones and work overload (15,42,57). GATA-4 actions involve combinatorial interactions with other cell-restricted or inducible transcription factors, including Nkx2.5, Mef2, SRF, nuclear factor of activated T cells, SMAD, and c-fos (reviewed in reference 73).…”

Section: Discussionmentioning

confidence: 99%

“…The recombinant proteins glutathione S-transferase (GST)-GATA-4 1-207, GST-GATA-4 329-440, and GST-GATA-4 329-440 with a 419-420, SS3AA mutation were produced as described previously (15). Five micrograms of bacterially expressed protein was incubated with 20 ng of the purified catalytic subunit of protein kinase C (Calbiochem) in the reaction buffer (20 mM Tris [pH 7.5], 12.5 mM MgCl 2 , 0.5 mM EGTA, 50 M ATP) at 30°C for 1 h. Thereafter, the proteins were resolved on 10% sodium dodecyl sulfatepolyacrylamide gel electrophoresis and exposed to X-ray films.…”

Section: Methodsmentioning

confidence: 99%

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Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

Wang

Paradis

Aries

et al. 2005

Molecular and Cellular Biology

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Angiotensin II (AII), a potent vasoactive hormone, acts on numerous organs via G-protein-coupled receptors and elicits cell-specific responses. At the level of the heart, AII stimulation alters gene transcription and leads to cardiomyocyte hypertrophy. Numerous intracellular signaling pathways are activated in this process; however, which of these directly link receptor activation to transcriptional regulation remains undefined. We used the atrial natriuretic factor (ANF) gene (NPPA) as a marker to elucidate the signaling cascades involved in AII transcriptional responses. We show that ANF transcription is activated directly by the AII type 1 receptor and precedes the development of myocyte hypertrophy. This response maps to STAT and GATA binding sites, and the two elements transcriptionally cooperate to mediate signaling through the JAK-STAT and protein kinase C (PKC)-GATA-4 pathways. PKC phosphorylation enhances GATA-4 DNA binding activity, and STAT-1 functionally and physically interacts with GATA-4 to synergistically activate AII and other growth factor-inducible promoters. Moreover, GATA factors are able to recruit STAT proteins to target promoters via GATA binding sites, which are sufficient to support synergy. Thus, STAT proteins can act as growth factor-inducible coactivators of tissue-specific transcription factors. Interactions between STAT and GATA proteins may provide a general paradigm for understanding cell specificity of cytokine and growth factor signaling.

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“…Furthermore, Rho GTPases promote the transcription and expression of cyclin D1, which is directly related to cell cycle entry and enables aberrant cell growth of tumoral cells (Westwick et al, 1997;Danen et al, 2000;Welsh et al, 2001). Additional transcriptional regulatory effects and transcription factors modulated by Rho GTPases have been described and thoroughly reviewed (Van Aelst and D'Souza-Schorey, 1997;Aznar and Lacal, 2001a,b;Charron et al, 2001;Delarue et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

Benitah¹,

Valerón²,

Rui

et al. 2003

MBoC

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The involvement of Rho GTPases in signal transduction pathways leading to transcription activation is one of the major roles of this family of GTPases. Thus, the identification of transcription factors regulated by Rho GTPases and the understanding of the mechanisms of their activation and its biological outcome are of great interest. Here, we provide evidence that Rho GTPases modulate Stat5a, a transcription factor of the family of signal transducers and activators of transcription. RhoA triggers tyrosine phosphorylation (Y696) of Stat5a via a JAK2-dependent mechanism and promotes DNA-binding activity of Stat5a. Tyrosine phosphorylation of Stat5a is also stimulated physiologically by lysophosphatidic acid (LPA) in a Rho-dependent manner. Simultaneously, RhoA reduces serine phosphorylation of Stat5a at both serine residues S726 and S780, resulting in a further increase of activity as defined by mutagenesis experiments. Furthermore, serine dephosphorylation of Stat5a by RhoA does not take place by down-modulation of either JNK1, MEK1, or p38 MAP kinases, as determined by transfection experiments or chemical inhibition of both MEK1, p38, and JNK serine kinases. Thus, RhoA regulates Stat5a via tyrosine phosphorylation and via a yet to be determined novel down-modulating pathway that involves serine dephosphorylation. Finally, we provide evidence for a role of Stat5a in RhoA-induced epithelial-to-mesenchymal transition with concomitant increase in vimentin expression, E-cadherin down-regulation, and cell motility

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Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA

Cited by 204 publications

References 84 publications

Mitochondrial Reactive Oxygen Species Mediate Cardiomyocyte Formation from Embryonic Stem Cells in High Glucose

Mitochondrial Reactive Oxygen Species Mediate Cardiomyocyte Formation from Embryonic Stem Cells in High Glucose

Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

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