A Rac1 Effector Site Controlling Mitogenesis through Superoxide Production

Joneson, Tom; Bar–Sagi, Dafna

doi:10.1074/jbc.273.29.17991

Cited by 178 publications

(179 citation statements)

References 27 publications

Supporting

Mentioning

164

Contrasting

Unclassified

Order By: Relevance

“…At very early stages of differentiation and during gastrulation, the GTPase may thus be critical to facilitate proliferation and migration of cells, including muscle precursors (Sugihara et al, 1998;Settleman, 1999Settleman, , 2000Settleman, , 2001Knight et al, 2000), while preventing cell differentiation of one of the earliest cell types developing in the embryo, namely, the cardioblast. This could be mediated partially by ROS and NF B pathways (Joneson and Bar-Sagi, 1998;Babior, 1999;Joyce et al, 1999). Rac-induced ROS may also be critical for the physiological apoptotic process that occurs during early stages of embryogenesis (Pampfer, 2000;Poelmann et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

A Dual Role of the GTPase Rac in Cardiac Differentiation of Stem Cells

Pucéat¹,

Travo²,

Quinn³

et al. 2003

MBoC

View full text Add to dashboard Cite

The function of the GTPase Rac1, a molecular switch transducing intracellular signals from growth factors, in differentiation of a specific cell type during early embryogenesis has not been investigated. To address the question, we used embryonic stem (ES) cells differentiated into cardiomyocytes, a model that faithfully recapitulates early stages of cardiogenesis. Overexpression in ES cells of a constitutively active Rac (RacV12) but not of an active mutant (RacL61D38), which does not activate the NADPH oxydase generating ROS, prevented MEF2C expression and severely compromised cardiac cell differentiation. This resulted in poor expression of ventricular myosin light chain 2 (MLC2v) and its lack of insertion into sarcomeres. Thus ES-derived cardiomyocytes featured impaired myofibrillogenesis and contractility. Overexpression of MEF2C or addition of catalase in the culture medium rescued the phenotype of racV12 cells. In contrast, RacV12 specifically expressed in ES-derived ventricular cells improved the propensity of cardioblasts to differentiate into beating cardiomyocytes. This was attributed to both a facilitation of myofibrillogenesis and a prolongation in their proliferation. The dominant negative mutant RacN17 early or lately expressed in ES-derived cells prevented myofibrillogenesis and in turn beating of cardiomyocytes. We thus suggest a stage-dependent function of the GTPase during early embryogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

A Dual Role of the GTPase Rac in Cardiac Differentiation of Stem Cells

Pucéat¹,

Travo²,

Quinn³

et al. 2003

MBoC

View full text Add to dashboard Cite

show abstract

“…25 In contrast, the critical role of histidine 103 (H103) and lysine 166 (K166) of Rac1 protein in O 2 KÀ production has been established. 26 Note that these mutants are the same as those we used to demonstrate that O 2 KÀ production was involved in Rac1-mediated survival.…”

Section: Kàmentioning

confidence: 99%

Reactive oxygen species-mediated regulation of the Na+–H+ exchanger 1 gene expression connects intracellular redox status with cells' sensitivity to death triggers

et al. 2005

View full text Add to dashboard Cite

We have previously demonstrated that a slight increase in intracellular superoxide (O 2 KÀ ) anion confers resistance to death stimuli. Using pharmacological and molecular approaches to manipulate intracellular O 2 KÀ , here we report that an increase in intracellular O 2 KÀ anion induces Na þ /H þ exchanger 1 (NHE-1) gene promoter activity resulting in increased NHE-1 protein expression, which strongly correlates with the resistance of cells to death stimuli. In contrast, exposure to exogenous hydrogen peroxide suppressed NHE-1 promoter activity and gene expression, and increased cell sensitivity to death triggers. Furthermore, the increase in cell sensitivity to death upon downregulation of NHE-1 gene expression correlates with reduced capacity of cells to recover from an acid load, while survival upon overexpression of NHE-1 appears independent of its pump activity. These findings indicate that NHE-1 is a redox-regulated gene, and provide a novel intracellular target for the redox control of cell death sensitivity.

show abstract

“…The farnesylated Ras proteins, on the other hand, are associated with cell proliferation (Khosravi-Far and Der, 1994;Prendergast and Gibbs, 1993;Pronk and Bos, 1994). It has been shown that activation of Rho proteins are also necessary for cell proliferation (Hirai et al, 1997;Hill et al, 1995;Joneson and Bar-Sagi, 1998;Olson et al, 1998). These proteins have also been found to activate the JNK/SAPK signaling pathway in a celltype speci®c manner (Zhang et al, 1995;Coso et al, 1995;Teramoto et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line

et al. 1999

View full text Add to dashboard Cite

Prostate cancer cells derived from transgenic mice with adenocarcinoma of the prostate (TRAMP cells) were treated with the HMG-CoA reductase inhibitor, lovastatin. This caused inactivation of the small GTPase RhoA, actin stress ®ber disassembly, cell rounding, growth arrest in the G1 phase of the cell cycle, cell detachment and apoptosis. Addition of geranylgeraniol (GGOL) in the presence of lovastatin, to stimulate protein geranylgeranylation, prevented lovastatin's e ects. That is, RhoA was activated, actin stress ®bers were assembled, the cells assumed a¯at morphology and cell growth resumed. The following observations support an essential role for RhoA in TRAMP cell growth: (1) TRAMP cells expressing dominant-negative RhoA (T19N) mutant protein displayed few actin stress ®bers and grew at a slower rate than controls (35 h doubling time for cells expressing RhoA (T19N) vs 20 h for untransfected cells); (2) TRAMP cells expressing constitutively active RhoA (Q63L) mutant protein displayed a contractile phenotype and grew faster than controls (13 h doubling time). Interestingly, addition of farnesol (FOL) with lovastatin, to stimulate protein farnesylation, prevented lovastatin-induced cell rounding, cell detachment and apoptosis, and stimulated cell spreading to a spindle shaped morphology. However, RhoA remained inactive and growth arrest persisted. The morphological e ects of FOL addition were prevented in TRAMP cells expressing dominant-negative H-Ras (T17N) mutant protein. Thus, it appears that H-Ras is capable of inducing cell spreading, but incapable of supporting cell proliferation, in the absence of geranylgeranylated proteins like RhoA.

show abstract

A Rac1 Effector Site Controlling Mitogenesis through Superoxide Production

Cited by 178 publications

References 27 publications

A Dual Role of the GTPase Rac in Cardiac Differentiation of Stem Cells

A Dual Role of the GTPase Rac in Cardiac Differentiation of Stem Cells

Reactive oxygen species-mediated regulation of the Na+–H+ exchanger 1 gene expression connects intracellular redox status with cells' sensitivity to death triggers

Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line

Contact Info

Product

Resources

About