PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1

Simeone-Penney, Marina C.; Severgnini, Mariano; Rozo, Lilliana; Takahashi, Satoe; Cochran, Brent; Simon, Amy

doi:10.1152/ajplung.00529.2007

Cited by 73 publications

(71 citation statements)

References 51 publications

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“…Consistent with this study, our results point to active Rac1 increasing IL6 production. In contrast to Faruqi et al, but similar to other previous reports (Simon et al, 2000;Simeone-Penney et al, 2008), Figure 5. Tripolide inhibits tumor formation in nude mice.…”

Section: Discussionsupporting

confidence: 87%

“…Triptolide inactivated Rac1, a small GTPase in the Rho family that has clear roles in carcinogenesis. Rac1 is implicated in regulation of cell cycle regulators (Simeone-Penney et al, 2008), and we found that inhibition of Rac1 activation with a dominant negative allele reduced levels of CyclinD1 and CDK4. Thus, even if the evidence is indirect, a possible hypothesis for the G1 arrest seen when the colon carcinoma lines were treated with triptolide, is that active Rac1 was suppressed, leading to lower levels of cell cycle target genes.…”

Section: Discussionmentioning

confidence: 70%

“…Rac1 has been implicated in the regulation of STAT3 transcriptional activity, either indirectly (Faruqi et al, 2001), or through direct binding to STAT3 that promotes activating phosphorylation and nuclear localization (Simon et al, 2000;Simeone-Penney et al, 2008). Given the effect of triptolide on STAT3 phosphorylation and Rac1 activation, and the functional connection between Rac1 and STAT3, we examined cross-talk between Rac1 and the JAK/STAT pathway.…”

Section: Triptolide Affects Il6-jak/stat Via Rac1mentioning

confidence: 99%

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Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression

et al. 2009

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Triptolide, a diterpenoid triepoxide from the traditional Chinese medicinal herb Tripterygium wilfordii Hook. f., is a potential treatment for autoimmune diseases as well a possible anti-tumor agent. It inhibits proliferation of coloretal cancer cells in vitro and in vivo. In this study, its ability to block progress of colitis to colon cancer, and its molecular mechanism of action are investigated. A mouse model for colitis-induced colorectal cancer was used to test the effect of triptolide on cancer progression. Treatment of mice with triptolide decreased the incidence of colon cancer formation, and increased survival rate. Moreover, triptolide decreased the incidence of tumors in nude mice inoculated with cultured colon cancer cells dose-dependently. In vitro, triptolide inhibited the proliferation, migration and colony formation of colon cancer cells. Secretion of IL6 and levels of JAK1, IL6R and phosphorylated STAT3 were all reduced by triptolide treatment. Triptolide prohibited Rac1 activity and blocked cyclin D1 and CDK4 expression, leading to G1 arrest. Triptolide interrupted the IL6R-JAK/STAT pathway that is crucial for cell proliferation, survival, and inflammation. This suggests that triptolide might be a candidate for prevention of colitis induced colon cancer because it reduces inflammation and prevents tumor formation and development.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 70%

Section: Triptolide Affects Il6-jak/stat Via Rac1mentioning

confidence: 99%

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Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression

et al. 2009

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“…27 Plateletderived growth factor has been shown to regulate cell cycle progress by inducing Ccnd3 expression. 28,29 Thus, the observed low expression of Pdgfra after NAL treatment is consistent with the observed low expression of Ccnd3.…”

Section: Proliferation Of Progenitor Leydig Cellssupporting

confidence: 83%

Effects of luteinizing hormone and androgen on the development of rat progenitor Leydig cells in vitro and in vivo

Guo¹,

Ma²,

Wang³

et al. 2013

Asian J Androl

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Progenitor Leydig cells are derived from stem cells. The proliferation and differentiation of progenitor Leydig cells significantly contributes to Leydig cell number during puberty. However, the regulation of these processes remains unclear. The objective of the present study was to determine whether luteinizing hormone (LH) or androgen contributes to the proliferation and differentiation of progenitor Leydig cells. Fourteen-day-old male Sprague-Dawley rats were treated for 7 days with NalGlu, which is a gonadotropinreleasing hormone antagonist, to reduce the secretion of LH in the pituitary and thus, androgen in the testis. Rats were co-administered with LH or 7a-methyl-nortestosterone (MENT), which is an androgen resistant to metabolism by 5a-reductase 1 in progenitor Leydig cells, and the subsequent effects of LH or androgen were measured.3 H-Thymidine was also intravenously injected into rats to study thymidine incorporation in progenitor Leydig cells. Progenitor Leydig cells were examined. NalGlu administration reduced progenitor Leydig cell proliferation by 83%. In addition, LH or MENT treatment restored Leydig cell proliferative capacity to 73% or 50% of control, respectively. The messenger RNA levels of proliferation-related genes were measured using real-time PCR. The expression levels of Igf1, Lifr, Pdgfra, Bcl2, Ccnd3 and Pcna were upregulated by MENT, and those of Pdgfra, Ccnd3 and Pcna were upregulated by LH. Both LH and MENT stimulated the differentiation of progenitor Leydig cells in vitro. We concluded that both LH and MENT were involved in regulating the development of progenitor Leydig cells.

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“…Mechanical stress in airways can also induce EGF release from epithelial cells and thus contribute to remodeling (283). Emerging data suggest a role for the nonreceptor tyrosine kinase Abl, which appears to inhibit ERK1 phosphorylation, modulate actin dynamics, and further prevent the mitogenic effects of factors such as endothelin-1 and PDGF (138,139), the latter well known to be mitogenic in ASM (286). Other growth factors such as VEGF (187) and even the neurotrophin BDNF (5) can enhance ASM proliferation.…”

Section: L921mentioning

confidence: 99%

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Prakash

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

177

154

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Prakash YS. Airway smooth muscle in airway reactivity and remodeling: what have we learned? Am J Physiol Lung Cell Mol Physiol 305: L912-L933, 2013. First published October 18, 2013 doi:10.1152/ajplung.00259.2013.-It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca 2ϩ ]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro-vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.

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PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1

Abstract: Simeone-Penney MC, Severgnini M, Rozo L, Takahashi S, Cochran BH, Simon AR. PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1.

Cited by 73 publications

References 51 publications

Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression

Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression

Effects of luteinizing hormone and androgen on the development of rat progenitor Leydig cells in vitro and in vivo

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

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