Rnd3/RhoE induces tight junction formation in mammary epithelial tumor cells

Rubenstein, Nicola M.; Chan, James F.; Kim, Joseph Y.; Hansen, Steen Ingemann; Firestone, Gary L.

doi:10.1016/j.yexcr.2004.12.010

Cited by 22 publications

(18 citation statements)

References 53 publications

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“…We further established that the glucocorticoid down-regulation of the small GTPase RhoA is required for formation of organized intercellular junctions [10]. Our recent evidence shows that the functional ratio of RhoA to Rnd3/RhoE, a recently discovered natural RhoA antagonist, controls both adherens junction formation and tight junction sealing [11], suggesting that key downstream effectors of RhoA and Rnd3/RhoE signaling may be regulated in a steroiddependent manner.…”

Section: Introductionmentioning

confidence: 73%

“…Treatment with Rho kinase inhibitor Y-27632 disrupted the Rnd3/RhoE induced cell-cell interactions suggesting that the Rho kinases are down-stream effectors of Rnd3/RhoE. Because increasing the Rnd3/RhoE to RhoA ratio mimics the effects of glucocorticoids on apical junction formation and tight junction sealing [11], and ROCK2 is the predominant active Rho kinase in glucocorticoid-treated cells, we further propose that ROCK2 is likely to be the Rho kinase isoform that is downstream of Rnd3/RhoE. Consistent with our overall observations that Rho kinase activity is important for the glucocorticoidregulated cell-cell interactions, in endothelial cells and in intestinal epithelial cells the pharmacological inhibition of Rho kinase activity lead to loss of tight junction integrity and increased intercellular leakiness [18,19].…”

Section: Inhibition Of Rho Kinase Activity Ablates Both the Glucocortmentioning

confidence: 98%

“…We previously showed that ectopic expression of the RhoA antagonist Rnd3/RhoE induces apical junction organization and tight junction sealing of mammary epithelial tumor cells in the absence of glucocorticoids [11]. Treatment with Rho kinase inhibitor Y-27632 disrupted the Rnd3/RhoE induced cell-cell interactions suggesting that the Rho kinases are down-stream effectors of Rnd3/RhoE.…”

Section: Inhibition Of Rho Kinase Activity Ablates Both the Glucocortmentioning

confidence: 98%

“…We have previously shown that tight junctions sealing of monolayers of Con8 mammary epithelial tumor cells can be stimulated by either treatment with glucocorticoids [6][7][8][9][10]20,23] or by expression of the Rnd3/RhoE antagonist of RhoA [11]. To determine whether Rho kinase activity plays a role in the stimulation of cell-cell interactions by either glucooorticoids or Rnd3/RhoE, the effects Y-27632, a relatively specific pharmacological inhibitor of Rho kinase activity [25], was analyzed on tight junction sealing.…”

Section: Inhibition Of Rho Kinase Activity Ablates Both the Glucocortmentioning

confidence: 99%

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Selective glucocorticoid control of Rho kinase isoforms regulate cell–cell interactions

Rubenstein

Callahan

et al. 2007

Biochemical and Biophysical Research Communications

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The two Rho kinase isoforms ROCK1 and ROCK2 are downstream effectors of the small GTPase RhoA, although relatively little is known about potential isoform specific functions or the selective control of their cellular activities. Using Con8 rat mammary epithelial cells, we show that the synthetic glucocorticoid dexamethasone strongly stimulates the level of ROCK2 protein, which accounts for the increase in total cellular ROCK2 activity, whereas, steroid treatment down-regulated ROCK1 specific kinase activity without altering ROCK1 protein levels. In Con8 cells, the glucocorticoid induced formation of tight junctions requires the steroid-mediated down-regulation RhoA and function of the RhoA antagonist Rnd3. Treatment with the ROCK inhibitor Y-27632 ablated both the glucocorticoid-induced and Rnd3-mediated stimulation in tight junction sealing. Taken together, our results demonstrate that the expression and activity of ROCK1 and ROCK2 can be uncoupled in a signal-dependent manner, and further implicate a new function for ROCK2 in the steroid control of tight junction dynamics.

show abstract

Section: Introductionmentioning

confidence: 73%

Section: Inhibition Of Rho Kinase Activity Ablates Both the Glucocortmentioning

confidence: 98%

Section: Inhibition Of Rho Kinase Activity Ablates Both the Glucocortmentioning

confidence: 98%

Section: Inhibition Of Rho Kinase Activity Ablates Both the Glucocortmentioning

confidence: 99%

See 2 more Smart Citations

Selective glucocorticoid control of Rho kinase isoforms regulate cell–cell interactions

Rubenstein

Callahan

et al. 2007

Biochemical and Biophysical Research Communications

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“…Rnd3 overexpression can inhibit the RhoA‐ROCK signaling pathway by suppressing RhoA activity through a p190RhoGAP‐dependent pathway, as well as by binding to and inhibiting downstream ROCK I signaling 32, 33. This Rnd3‐mediated inhibition of RhoA has also been shown to enhance tight junction barrier function in mammary epithelial cells 34, 35. In endothelial cells, Rnd3 overexpression was reported to initially reduce actin stress fibers, but after 24 hours result in elevated actin stress fiber formation and changes in junctional structure due to upregulation of RhoB 36.…”

Section: Introductionmentioning

confidence: 99%

Rnd3 as a Novel Target to Ameliorate Microvascular Leakage

Breslin

Daines

Doggett

et al. 2016

JAHA

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BackgroundMicrovascular leakage of plasma proteins is a hallmark of inflammation that leads to tissue dysfunction. There are no current therapeutic strategies to reduce microvascular permeability. The purpose of this study was to identify the role of Rnd3, an atypical Rho family GTPase, in the control of endothelial barrier integrity. The potential therapeutic benefit of Rnd3 protein delivery to ameliorate microvascular leakage was also investigated.Methods and ResultsUsing immunofluorescence microscopy, Rnd3 was observed primarily in cytoplasmic areas around the nuclei of human umbilical vein endothelial cells. Permeability to fluorescein isothiocyanate–albumin and transendothelial electrical resistance of human umbilical vein endothelial cell monolayers served as indices of barrier function, and RhoA, Rac1, and Cdc42 activities were determined using G‐LISA assays. Overexpression of Rnd3 significantly reduced the magnitude of thrombin‐induced barrier dysfunction, and abolished thrombin‐induced Rac1 inactivation. Depleting Rnd3 expression with siRNA significantly extended the time course of thrombin‐induced barrier dysfunction and Rac1 inactivation. Time‐lapse microscopy of human umbilical vein endothelial cells expressing GFP‐actin showed that co‐expression of mCherry‐Rnd3 attenuated thrombin‐induced reductions in local lamellipodia that accompany endothelial barrier dysfunction. Lastly, a novel Rnd3 protein delivery method reduced microvascular leakage in a rat model of hemorrhagic shock and resuscitation, assessed by both intravital microscopic observation of extravasation of fluorescein isothiocyanate–albumin from the mesenteric microcirculation, and direct determination of solute permeability in intact isolated venules.ConclusionsThe data suggest that Rnd3 can shift the balance of RhoA and Rac1 signaling in endothelial cells. In addition, our findings suggest the therapeutic, anti‐inflammatory potential of delivering Rnd3 to promote endothelial barrier recovery during inflammatory challenge.

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Rnd proteins: Multifunctional regulators of the cytoskeleton and cell cycle progression

2010

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Rnd3/RhoE has two distinct functions, regulating the actin cytoskeleton and cell proliferation. This might explain why its expression is often altered in cancer and by multiple stimuli during development and disease. Rnd3 together with its relatives Rnd1 and Rnd2 are atypical members of the Rho GTPase family in that they do not hydrolyse GTP. Rnd3 and Rnd1 both antagonise RhoA/ROCK-mediated actomyosin contractility, thereby regulating cell migration, smooth muscle contractility and neurite extension. In addition, Rnd3 has been shown to have a separate role in inhibiting cell cycle progression by reducing translation of cell cycle regulators, including cyclin D1 and Myc. We propose that Rnd3 could act as a tumour suppressor to limit proliferation, but when mutations bypass this activity of Rnd3, it can promote cancer invasion through its effects in the actin cytoskeleton.

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Rnd3/RhoE induces tight junction formation in mammary epithelial tumor cells

Cited by 22 publications

References 53 publications

Selective glucocorticoid control of Rho kinase isoforms regulate cell–cell interactions

Selective glucocorticoid control of Rho kinase isoforms regulate cell–cell interactions

Rnd3 as a Novel Target to Ameliorate Microvascular Leakage

Rnd proteins: Multifunctional regulators of the cytoskeleton and cell cycle progression

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