Induction of small G protein RhoB by non‐genotoxic stress inhibits apoptosis and activates NF‐κB

Li, Yidong; Liu, Yaping; Cao, Dongmei; Yan, Yongmei; Hou, You-Na; Zhao, Jie-Ying; Yang, Rui; Xia, Zhaofan; Lü, Jing

doi:10.1002/jcp.22394

Cited by 23 publications

(17 citation statements)

References 54 publications

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“…RhoB is the only member of Rho GTPase family of proteins that is rapidly and transiently upregulated in response to stress conditions 12,47 and our results show that increased RhoB activity has a protective effect on pulmonary vascular cells under conditions of limited oxygen supply. Establishing upstream activators of RhoB will require further studies.…”

Section: Discussionmentioning

confidence: 54%

Role of RhoB in the Regulation of Pulmonary Endothelial and Smooth Muscle Cell Responses to Hypoxia

Wójciak-Stothard

Zhao

Oliver

et al. 2012

Circulation Research

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Rationale RhoA and Rho kinase contribute to pulmonary vasoconstriction and vascular remodeling in pulmonary hypertension. RhoB, a protein homologous to RhoA and activated by hypoxia, regulates neoplastic growth and vasoconstriction but its role in the regulation of pulmonary vascular function is not known. Objective To determine the role of RhoB in pulmonary endothelial and smooth muscle cell responses to hypoxia and in pulmonary vascular remodeling in chronic hypoxia-induced pulmonary hypertension. Methods and Results Hypoxia increased expression and activity of RhoB in human pulmonary artery endothelial and smooth muscle cells, coincidental with activation of RhoA. Hypoxia or adenoviral overexpression of constitutively activated RhoB increased actomyosin contractility, induced endothelial permeability, and promoted cell growth; dominant negative RhoB or manumycin, a farnesyltransferase inhibitor that targets the vascular function of RhoB, inhibited the effects of hypoxia. Coordinated activation of RhoA and RhoB maximized the hypoxia-induced stress fiber formation caused by RhoB/mammalian homolog of Drosophila diaphanous-induced actin polymerization and RhoA/Rho kinase-induced phosphorylation of myosin light chain on Ser19. Notably, RhoB was specifically required for hypoxia-induced factor-1α stabilization and for hypoxia-and platelet-derived growth factor-induced cell proliferation and migration. RhoB deficiency in mice markedly attenuated development of chronic hypoxia-induced pulmonary hypertension, despite compensatory expression of RhoA in the lung. Conclusions RhoB mediates adaptational changes to acute hypoxia in the vasculature, but its continual activation by chronic hypoxia can accentuate vascular remodeling to promote development of pulmonary hypertension. RhoB is a potential target for novel approaches (eg, farnesyltransferase inhibitors) aimed at regulating pulmonary vascular tone and structure. (Circ Res. 2012;110:1423–1434.)

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Section: Discussionmentioning

confidence: 54%

Role of RhoB in the Regulation of Pulmonary Endothelial and Smooth Muscle Cell Responses to Hypoxia

Wójciak-Stothard

Zhao

Oliver

et al. 2012

Circulation Research

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“…The p38 pathway has been particularly linked to the promotion of increased mRNA stabilization of numerous inflammatory genes, such as IL-1, IL-6, IL-8, VEGF, TNFα, and COX-2 [4]. Our previous study showed that p38 pathway is involved in heat stress-induced RhoB expression in human lung carcinoma cell line A549 [19]. In the present study, we found that Dex can activate Akt and p38 in MG-63 cells.…”

Section: Discussionmentioning

confidence: 99%

Involvement of small G protein RhoB in the regulation of proliferation, adhesion and migration by dexamethasone in osteoblastic cells

et al. 2017

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Long-term exposure to therapeutic doses of glucocorticoids (GCs) results in bone remodeling, which frequently causes osteoporosis and fracture healing retardation because of the abnormality of osteoblastic proliferation and differentiation. The mechanisms of GCs’ effect on osteoblasts are largely unknown. In this present study, we found that dexamethasone (Dex) could induce the expression of the small G protein, RhoB, in mRNA and protein levels in the osteoblast-derived osteosarcoma cell lines MG-63. The up-regulation of RhoB mRNA by Dex mainly occurs at posttranscriptional level by increasing its mRNA stability through PI-3K/Akt and p38 mitogen-activated protein kinase signaling pathways. Over-expression of RhoB in MG-63 cells magnified while down-regulation of RhoB level by RNA interference impaired Dex-induced growth inhibition but not differentiation. What’s more, over-expression of RhoB mimicked the effect of Dex on cell adhesion and migration. And interfering RhoB expression partially suppressed Dex-induced pro-adhesion and anti-migration in MG-63 cells. In conclusion, these results indicate that RhoB plays an important role in the pathological effect of Dex on osteoblastic growth and migration, which is a part of the mechanisms of GCs’ adverse effect on bone remodeling.

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“…RhoB is involved in endocytosis and vesicle trafficking, it therefore contributes to the cytoplasmic membrane targeting of a variety of receptors and signalling molecules such as epidermal growth factor receptor, platelet‐derived growth factor receptor, non‐receptor kinases src and Akt in cells . RhoB can be rapidly up‐regulated by cytokines or growth factors, such as TGF‐β and be activated by genotoxic stress and heat stress . It is considered a stress sensor and plays an important role in the regulation of cytoskeletal organization, cell proliferation, cell survival and tumour invasiveness .…”

Section: Introductionmentioning

confidence: 99%

The mechanisms and significance of up‐regulation of RhoB expression by hypoxia and glucocorticoid in rat lung and A549 cells

Huang

Pan

Jin

et al. 2016

J Cellular Molecular Medi

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Small guanosine triphosphate (GTP)‐binding protein RhoB is an important stress sensor and contributes to the regulation of cytoskeletal organization, cell proliferation and survival. However, whether RhoB is involved in the hypoxic response and action of glucocorticoid (GC) is largely unknown. In this study, we investigated the effects of hypoxia or/and GC on the expression and activition of RhoB in the lung of rats and human A549 lung carcinoma cells, and further studied its mechanism and significance. We found that hypoxia and dexamethasone (Dex), a synethic GC, not only significantly increased the expression and activation of RhoB independently but also coregulated the expresion of RhoB in vitro and in vivo. Up‐regulation of RhoB by hypoxia was in part through stabilizing the RhoB mRNA and protein. Inhibiting hypoxia‐activated hypoxia‐inducible transcription factor‐1α (HIF‐1α), c‐Jun N‐terminal kinase (JNK) or extracellular signal‐regulated kinase (ERK) with their specific inhibitors significantly decreased hypoxia‐induced RhoB expression, indicating that HIF‐1α, JNK and ERK are involved in the up‐regulation of RhoB in hypoxia. Furthermore, we found that knockdown of RhoB expression by RhoB siRNA not only significantly reduced hypoxia‐enhanced cell migration and cell survival in hypoxia but also increased the sensitivity of cell to paclitaxel (PTX), a chemotherapeutic agent, and reduced Dex‐enhanced resistance to PTX‐chemotherapy in A549 cells. Taken together, the novel data revealed that hypoxia and Dex increased the expression and activation of RhoB, which is important for hypoxic adaptation and hypoxia‐accelerated progression of lung cancer cells. RhoB also enhanced the resistance of cell to PTX‐chemotherapy and mediated the pro‐survival effect of Dex.

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Induction of small G protein RhoB by non‐genotoxic stress inhibits apoptosis and activates NF‐κB

Cited by 23 publications

References 54 publications

Role of RhoB in the Regulation of Pulmonary Endothelial and Smooth Muscle Cell Responses to Hypoxia

Role of RhoB in the Regulation of Pulmonary Endothelial and Smooth Muscle Cell Responses to Hypoxia

Involvement of small G protein RhoB in the regulation of proliferation, adhesion and migration by dexamethasone in osteoblastic cells

The mechanisms and significance of up‐regulation of RhoB expression by hypoxia and glucocorticoid in rat lung and A549 cells

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