Manumycin A, Inhibitor of ras Farnesyltransferase, Inhibits Proliferation and Migration of Rat Vascular Smooth Muscle Cells

Kouchi, Hirosuke; Nakamura, Kazufumi; Fushimi, Kazuo; Sakaguchi, Masakiyo; Miyazaki, Masahiro; Ohe, Tohru; Namba, Masayoshi

doi:10.1006/bbrc.1999.1546

Cited by 44 publications

(34 citation statements)

References 25 publications

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“…Our experiments on cells lacking lamin A strongly suggest that some of the beneficial effects of FTI treatment are caused by targeting farnesylated proteins other than lamin A/progerin. Previous reports demonstrate an inhibitory effect of FTI on cell proliferation and migration at high doses (Kouchi et al, 1999;Kusama et al, 2003Kusama et al, , 2006Desrosiers et al, 2005). Our data, using lower doses of FTI, support the inhibitory effect of FTI on proliferation.…”

Section: Discussionsupporting

confidence: 86%

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

et al. 2008

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SummaryHutchinson-Gilford progeria syndrome (HGPS), reportedly a model for normal aging, is a genetic disorder in children marked by dramatic signs suggestive for premature aging. It is usually caused by de novo mutations in the nuclear envelope protein lamin A. Lamins are essential to maintaining nuclear integrity, and loss of lamin A/C results in increased cellular sensitivity to mechanical strain and defective mechanotransduction signaling. Since increased mechanical sensitivity in vascular cells could contribute to loss of smooth muscle cells and the development of arteriosclerosis -the leading cause of death in HGPS patients -we investigated the effect of mechanical stress on cells from HGPS patients. We found that skin fibroblasts from HGPS patients developed progressively stiffer nuclei with increasing passage number. Importantly, fibroblasts from HGPS patients had decreased viability and increased apoptosis under repetitive mechanical strain, as well as attenuated wound healing, and these defects preceded changes in nuclear stiffness. Treating fibroblasts with farnesyltransferase inhibitors restored nuclear stiffness in HGPS cells and accelerated the wound healing response in HGPS and healthy control cells by increasing the directional persistence of migrating cells. However, farnesyltransferase inhibitors did not improve cellular sensitivity to mechanical strain. These data suggest that increased mechanical sensitivity in HGPS cells is unrelated to changes in nuclear stiffness and that increased biomechanical sensitivity could provide a potential mechanism for the progressive loss of vascular smooth muscle cells under physiological strain in HGPS patients.

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Section: Discussionsupporting

confidence: 86%

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

et al. 2008

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“…1 Approaches designed to block Ras-mediated smooth muscle cell proliferation and migration have been successful in several in vitro studies. 29 Moreover, studies that used gene delivery of dominant negative forms of ras have shown them to be effective in suppressing neointimal formation after experimental carotid injury. 30,31 It is thus possible that by altering the proliferative phenotype of atherosclerotic lesions, FTS could have induced suppression of atherosclerotic lesions.…”

Section: Discussionmentioning

confidence: 99%

Functional Inhibition of Ras by S - trans , trans -Farnesyl Thiosalicylic Acid Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice

George

Afek²,

Keren³

et al. 2002

Circulation

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Background-Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis. Methods and Results-We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E-deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes from the FTS-treated versus control mice exhibited reduced proliferation to oxidized LDL (OxLDL) but not to concanavalin A. IgG anti-OxLDL antibody levels were reduced in FTS-treated mice compared with controls. Whereas no effect of FTS was evident on plaque T lymphocyte and macrophage content, lesional vascular cell adhesion molecule-1 and nuclear factor-B expression were considerably reduced compared with controls. Conclusions-FTS

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“…H-Ras is expressed in smooth muscle cells, with a peak expression in proliferating cells in mid to late G 1 phase (403). Growth factors such as PDGF activate the Ras-MAPK pathway in vascular smooth muscle cells, and Ras inhibition by FTI or expression of dominant negative H-Ras mutant reduces proliferation (235,491). In contrast, introduction of the dominant active H-Ras-V12 in vascular smooth muscle cells induces a growth arrest with phenotypic characteristics of cellular senescence, suggesting that H-Ras signaling contributes to age-related vascular disorders (312).…”

Section: Ras Proteinsmentioning

confidence: 99%

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Loirand

Sauzeau

Pacaud

2013

Physiological Reviews

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Small G proteins exist in eukaryotes from yeast to human and constitute the Ras superfamily comprising more than 100 members. This superfamily is structurally classified into five families: the Ras, Rho, Rab, Arf, and Ran families that control a wide variety of cell and biological functions through highly coordinated regulation processes. Increasing evidence has accumulated to identify small G proteins and their regulators as key players of the cardiovascular physiology that control a large panel of cardiac (heart rhythm, contraction, hypertrophy) and vascular functions (angiogenesis, vascular permeability, vasoconstriction). Indeed, basal Ras protein activity is required for homeostatic functions in physiological conditions, but sustained overactivation of Ras proteins or spatiotemporal dysregulation of Ras signaling pathways has pathological consequences in the cardiovascular system. The primary object of this review is to provide a comprehensive overview of the current progress in our understanding of the role of small G proteins and their regulators in cardiovascular physiology and pathologies.

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Manumycin A, Inhibitor of ras Farnesyltransferase, Inhibits Proliferation and Migration of Rat Vascular Smooth Muscle Cells

Cited by 44 publications

References 25 publications

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

Functional Inhibition of Ras by S - trans , trans -Farnesyl Thiosalicylic Acid Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

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