RhoB Loss Prevents Streptozotocin-Induced Diabetes and Ameliorates Diabetic Complications in Mice

Bravo‐Nuevo, Arturo; Sugimoto, Hikaru; Iyer, Seema; Fallon, Zachary; Lucas, Jason M.; Kazerounian, Shiva; Prendergast, George C.; Kalluri, Raghu; Shapiro, Nathan I.; Benjamin, Laura E.

doi:10.1016/j.ajpath.2010.11.040

Cited by 14 publications

(12 citation statements)

References 23 publications

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“…In establishing a critical function for RhoB in tumor angiogenesis, our work points to future work in determining how this small GTPase influences responses to hypoxia and glucose deprivation, stresses of central relevance to cancer pathophysiology that other recent studies suggest RhoB may control (44, 45). Our findings reinforce the concept that genetic validation of a candidate target in the tumor stroma is critical to monitor, as effects at this level may dominate the desired effects on tumor cells and alter interpretations of what constitutes a suitable therapeutic candidate.…”

Section: Discussionmentioning

confidence: 70%

RhoB Differentially Controls Akt Function in Tumor Cells and Stromal Endothelial Cells during Breast Tumorigenesis

et al. 2013

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Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports to tumor pathophysiology but the distinct characteristics of their signaling networks are not usually considered in developing drugs to target tumors. This oversight potentially confounds proof-of-concept studies and increases drug development risks. Here, we show in established murine and human models of breast cancer how differential regulation of Akt by the small GTPase RhoB in cancer cells or stromal endothelial cells determines their dormancy versus outgrowth when angiogenesis becomes critical. In cancer cells in vitro or in vivo, RhoB functions as a tumor suppressor that restricts EGF receptor (EGFR) cell surface occupancy as well as Akt signaling. However, after activation of the angiogenic switch, RhoB functions as a tumor promoter by sustaining endothelial Akt signaling, growth, and survival of stromal endothelial cells that mediate tumor neoangiogenesis. Altogether, the positive impact of RhoB on angiogenesis and progression supercedes its negative impact in cancer cells themselves. Our findings elucidate the dominant positive role of RhoB in cancer. More generally, they illustrate how differential gene function effects on signaling pathways in the tumor stromal component can complicate the challenge of developing therapeutics to target cancer pathophysiology.

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Section: Discussionmentioning

confidence: 70%

RhoB Differentially Controls Akt Function in Tumor Cells and Stromal Endothelial Cells during Breast Tumorigenesis

et al. 2013

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“…In contrast, VEGF-C overexpression accelerated wound closure by inducing angiogenesis, lymphangiogenesis and recruitment of inflammatory cells in diabetic animals9. We recently observed a similar phenomenon in RhoB −/− diabetic mice38, suggesting that the impact of deregulation of angiogenesis and/or lymphangiogenesis by loss of RhoB could be exacerbated in pathological conditions such as those occurring in diabetic animals.…”

Section: Discussionmentioning

confidence: 74%

“…Although we were unable to evaluate the impact of the RhoB–VEZF1 pathway on wound closure in the ear model, our parallel study of dorsal skin excisional wound healing revealed that healthy RhoB − / − mice did not exhibit any significant difference in the time required for complete wound closure as compared with wt mice38. This result correlates with previous work, that is, earlier and increased lymphangiogenesis elicited by VEGF-A overexpression did not affect the time required for wound closure in healthy animals6.…”

Section: Discussionmentioning

confidence: 86%

RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription

et al. 2013

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Mechanisms governing the distinct temporal dynamics that characterize post-natal angiogenesis and lymphangiogenesis elicited by cutaneous wounds and inflammation remain unclear. RhoB, a stress-induced small GTPase, modulates cellular responses to growth factors, genotoxic stress and neoplastic transformation. Here we show, using RhoB null mice, that loss of RhoB decreases pathological angiogenesis in the ischaemic retina and reduces angiogenesis in response to cutaneous wounding, but enhances lymphangiogenesis following both dermal wounding and inflammatory challenge. We link these unique and opposing roles of RhoB in blood versus lymphatic vasculatures to the RhoB-mediated differential regulation of sprouting and proliferation in primary human blood versus lymphatic endothelial cells. We demonstrate that nuclear RhoB-GTP controls expression of distinct gene sets in each endothelial lineage by regulating VEZF1-mediated transcription. Finally, we identify a small-molecule inhibitor of VEZF1–DNA interaction that recapitulates RhoB loss in ischaemic retinopathy. Our findings establish the first intra-endothelial molecular pathway governing the phased response of angiogenesis and lymphangiogenesis following injury.

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“…RhoB is a stress-inducible member of the Rho family of small GTPases that influence membrane dynamics and the actin cytoskeleton ( Biro et al, 2014 ; Hall, 2012 ; Murali and Rajalingam, 2014 ; Thumkeo et al, 2013 ; Wheeler and Ridley, 2007 ). Unlike many other members of this family, RhoB is dispensable for development and normal physiology but critical for stress responses that modify disease processes ( Chen et al, 2006 ; Fritz et al, 1995 ; Huang et al, 2007 ; Liu et al, 2001 ; Prendergast, 2001 ; Adini et al, 2003 ; Bravo-Nuevo et al, 2011b ). Although RhoB has been studied little in adaptive immunity, the canonical Rho proteins Rac1, Cdc42 and RhoA, as well as their regulators and effectors, are recognized widely to participate in B- and T-cell development, activation, proliferation, differentiation and migration ( Biro et al, 2014 ; Reedquist and Tak, 2012 ; Saoudi et al, 2014 ; Tybulewicz and Henderson, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus

Mandik-Nayak

DuHadaway

Mulgrew

et al. 2017

Disease Models &Amp; Mechanisms

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During the development of autoimmune disease, a switch occurs in the antibody repertoire of B cells so that the production of pathogenic rather than non-pathogenic autoantibodies is enabled. However, there is limited knowledge concerning how this pivotal step occurs. Here, we present genetic and pharmacological evidence of a positive modifier function for the vesicular small GTPase RhoB in specifically mediating the generation of pathogenic autoantibodies and disease progression in the K/BxN preclinical mouse model of inflammatory arthritis. Genetic deletion of RhoB abolished the production of pathogenic autoantibodies and ablated joint inflammation in the model. Similarly, administration of a novel RhoB-targeted monoclonal antibody was sufficient to ablate autoantibody production and joint inflammation. In the MRL/lpr mouse model of systemic lupus erythematosus (SLE), another established preclinical model of autoimmune disease associated with autoantibody production, administration of the anti-RhoB antibody also reduced serum levels of anti-dsDNA antibodies. Notably, the therapeutic effects of RhoB blockade reflected a selective deficiency in response to self-antigens, insofar as RhoB-deficient mice and mice treated with anti-RhoB immunoglobulin (Ig) both mounted comparable productive antibody responses after immunization with a model foreign antigen. Overall, our results highlight a newly identified function for RhoB in supporting the specific production of pathogenic autoantibodies, and offer a preclinical proof of concept for use of anti-RhoB Ig as a disease-selective therapy to treat autoimmune disorders driven by pathogenic autoantibodies.

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RhoB Loss Prevents Streptozotocin-Induced Diabetes and Ameliorates Diabetic Complications in Mice

Cited by 14 publications

References 23 publications

RhoB Differentially Controls Akt Function in Tumor Cells and Stromal Endothelial Cells during Breast Tumorigenesis

RhoB Differentially Controls Akt Function in Tumor Cells and Stromal Endothelial Cells during Breast Tumorigenesis

RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription

RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus

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