Rho GTPase, Rac1, regulates Skp2 levels, vascular smooth muscle cell proliferation, and intima formation in vitro and in vivo

Bond, Mark; Wu, Yih‐Jer; Sala-Newby, Graciela B.; Newby, Andrew C.

doi:10.1093/cvr/cvn188

Cited by 58 publications

(65 citation statements)

References 34 publications

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“…RECK is downregulated by multiple signaling pathways at multiple levels ( Our data are consistent with the model that RECK inhibits cell division by protecting pericellular extracellular matrix (for example, collagens), thereby enhancing integrin signaling that leads to SKP2 downregulation and consequent p27 upregulation (Figure 6). The previous findings that Rac1 downregulates SKP2 in rat vascular smooth muscle cells (Bond et al, 2008) and that b1 integrin downregulates SKP2 and suppresses proliferation of the hepatocellular carcinoma line SMMC-7721 (Fu et al, 2007) are in agreement with this model. Not surprisingly, not all cancer cells respond in the same manner to b1 integrin.…”

Section: Discussionsupporting

confidence: 86%

Involvement of the SKP2–p27KIP1 pathway in suppression of cancer cell proliferation by RECK

et al. 2011

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The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in cancers; in some cases, a significant correlation between the level of residual RECK in resected tumors and patient survival has been noted. Furthermore, restoration of RECK expression in certain cancer-derived cell lines results in reduced tumorigenicity. Here we report that acute RECK expression in colon carcinoma cells results in cell cyclearrest accompanied by downregulation of a ubiquitin ligase component, S-phase kinase-associated protein 2 (SKP2), and upregulation of its substrate, p27 KIP1 . Our data indicate that RECK-induced growth suppression is at least partially dependent on p27, and that RECK and type I collagen share similar effects on the SKP2-p27 pathway. Importantly, in patients with lung, colorectal and bladder cancers, the RECK/SKP2 ratio is high in normal tissues and lower in the cancer tissues. These findings reveal a novel molecular pathway linking cellcycle progression to RECK downregulation, extracellular matrix degradation and SKP2 upregulation, and suggest that treatment regimens that induce RECK expression could be promising cancer therapies.

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Section: Discussionsupporting

confidence: 86%

Involvement of the SKP2–p27KIP1 pathway in suppression of cancer cell proliferation by RECK

et al. 2011

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“…Transgenic overexpression of dominant active Rac1-V12 confirmed the role of Rac1 as a regulator of the redox state of blood vessel (157). In the balloon injury model of vascular remodeling, Pak1 is found to be activated in neointima of injured rat carotid artery, and a marked reduction of the neointimal thickening is observed in dominant-negative Pak1 or Rac1 adenovirustreated artery (49,173). In diabetes-induced vascular injury linked to an increased oxidative stress and Rac1/Pak1 activity, dominant-negative Rac1 gene transfer has also been shown to be protective (498).…”

Section: Rho Proteinsmentioning

confidence: 66%

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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“…Rac1, a Rho GTPase, activity regulates VSMC proliferation by controlling S-phase kinase-associated protein-2 (Skp2) levels. 35 A previous study has indicated that atorvastatin could inhibit serotonin-induced VSMC mitogenesis and migration through targeting the Rho/ROCK pathway. 36 Treatment of primary cultured juvenile rat pulmonary artery VSMC with Y-27632, a ROCK inhibitor, attenuated VSMC proliferation and increased VSMC apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Monocrotaline-induced Pulmonary Arterial Hypertension in Rats by Rosuvastatin

Rui-jin

2012

Journal of Cardiovascular Pharmacology

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Rho GTPase, Rac1, regulates Skp2 levels, vascular smooth muscle cell proliferation, and intima formation in vitro and in vivo

Cited by 58 publications

References 34 publications

Involvement of the SKP2–p27KIP1 pathway in suppression of cancer cell proliferation by RECK

Involvement of the SKP2–p27KIP1 pathway in suppression of cancer cell proliferation by RECK

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

Attenuation of Monocrotaline-induced Pulmonary Arterial Hypertension in Rats by Rosuvastatin

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