Induction of β3-Integrin Gene Expression by Sustained Activation of the Ras-Regulated Raf–MEK–Extracellular Signal-Regulated Kinase Signaling Pathway

Woods, Douglas; Cherwinski, Holly; Venetsanakos, Eleni; Bhat, Arun; Gysin, Stephan; Humbert, M.; Bray, Paul F.; Saylor, Vicki; McMahon, Martin

doi:10.1128/mcb.21.9.3192-3205.2001

Cited by 118 publications

(86 citation statements)

References 90 publications

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“…The activation of MAP kinase and its downstream effectors in melanoma may support the autonomous growth of cancer cells, leading to uncontrolled proliferation, a hallmark of tumorigenesis. Furthermore, it has been shown that sustained activation of the MAP kinase pathway increases the expression of b3 integrin (Woods et al, 2001), a molecule correlated with the acquisition of invasive behavior by melanoma cells (Albelda et al, 1990;Hsu et al, 1998). Despite ample studies on the role of the PI3K-AKT pathway in various cancers (Aoki et al, 1998;Nicholson and Anderson, 2002) …”

Section: Resultsmentioning

confidence: 99%

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Reciprocal regulation of MelCAM and AKT in human melanoma

Kalabis

et al. 2003

Oncogene

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Alteration in the expression of invasion/metastasis-related melanoma cell adhesion molecule (MelCAM) is strongly associated with the acquisition of malignancy by human melanoma. However, little is known about the molecular and biochemical mechanisms that regulate the expression and function of MelCAM, or its downstream signaling transduction. In this study, we show that there is a reciprocal regulation loop between AKT and MelCAM. Pharmacological inhibition of AKT in human melanoma cell lines substantially reduced the expression of Mel-CAM. Overexpression of constitutively active AKT upregulated the levels of MelCAM in melanoma cell lines, whereas expression of a dominant-negative PI-3 kinase downregulated MelCAM. On the other hand, overexpression of MelCAM activated endogenous AKT and inhibited proapoptotic protein BAD in melanoma cells, leading to increased survival under stress conditions. Constitutive activation of AKT was observed in most melanoma cell lines and tumor samples of different progression stages. These data link AKT activation with MelCAM expression, and implicate that intervention of MelCAM-AKT signaling axis in melanoma is a potential therapeutical approach.

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Section: Resultsmentioning

confidence: 99%

“…It has been shown that continuous activation of the MAPK pathway induced b3 integrin expression in melanoma (Woods et al, 2001). However, it is not clear whether AKT activation plays a role in the regulation.…”

Section: Akt Activity Regulates Melcam Expression In Melanoma Cellsmentioning

confidence: 98%

Reciprocal regulation of MelCAM and AKT in human melanoma

Kalabis

et al. 2003

Oncogene

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“…These results clearly show that miRNA let-7a has a much more dramatic effect on integrin b 3 expression in our cell lines than promoter-dependent mechanisms do have. Woods et al (2001) published that the activation of integrin b 3 expression is induced by sustained activation of the Ras-regulated Raf-MEK-ERK signaling pathway in NIH 3T3 cells. Direct regulation of the integrin b 3 promoter by ERK-activated transcription factors can be ruled out by our promoter analysis.…”

Section: Let-7a Has Strong Impact On the Invasive Potential Of Melanomentioning

confidence: 99%

“…Experiments with reporter constructs containing regions upstream of the integrin b 3 transcription start showed that there is (1) a megakaryocytic cell-line-specific cis-acting element that regulates integrin b 3 expression in megakaryocytic cell lines, but is not effective in regulating the expression of integrin b 3 in endothelial and melanoma cell lines and (2) a sequence that is involved in the regulation of integrin b 3 also in the melanoma cell line WM793, most likely through the Sp1 transcription factor (Jin et al, 1998). Another study was able to show that sustained activation of the Ras-regulated Raf-MEK-extracellular signal-regulated kinase (ERK) signaling pathway induces integrin b 3 gene expression in NIH 3T3 cells (Woods et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Integrin β3 expression is regulated by let-7a miRNA in malignant melanoma

2008

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Although integrin b 3 is known to play an important role in melanoma progression and invasion, regulation of integrin b 3 expression in melanoma has not been analysed in detail until today. As transcriptional regulation of integrin b 3 was ruled out by our analysis, we concentrated on the regulation by microRNAs (miRNAs) . Comparing primary melanocytes and malignant melanoma cell lines, we found that one candidate miRNA, miR-let-7a, was lost in melanoma and sequence analysis suggested an interaction with the 3 0 -untranslated region (3 0 -UTR) of integrin b 3 mRNA. Transfection of melanoma cells with let-7a pre-miR TM molecules resulted in the downregulation of integrin b 3 mRNA and protein expression. In addition, we cloned the 3 0 -UTR of the integrin b 3 mRNA containing the let-7a target sequence into a reporter plasmid and revealed that let-7a negatively regulates reporter gene expression. The repressed expression of integrin b 3 accompanies with reduced invasive potential of melanoma cells transfected with synthetic let-7a molecules observed in Boyden chamber assays. On the other hand, the induction of integrin b 3 expression was achieved in melanocytes by transfection with let-7a anti-miRs, resulting in invasive behavior of transfected melanocytes. In summary, we determined miRNA let-7a to be an important regulator of integrin b 3 expression and showed that the loss of let-7a expression is involved in development and progression of malignant melanoma.

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“…Depending on the cell cycle and costimulatory events, activation of c-Raf-1 can result in a variety of counteracting cellular responses such as proliferation, growth arrest, induction of apoptosis, or differentiation (11)(12)(13). Of interest in RA, c-Raf-1 has also been associated with the up-regulation of adhesion molecules such as integrins (14). C-Raf-1 is activated mainly by Ras in response to signals from growth factor receptors such as epidermal growth factor (EGF), but it is also regulated by signaling pathways involving the tumor suppressor PTEN (15) and the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt (protein kinase B) signaling pathway (16).…”

mentioning

confidence: 99%

Cooperation of Ras‐ and c‐Myc–dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in rheumatoid arthritis

Pap

Nawrath

Heinrich

et al. 2004

Arthritis & Rheumatism

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Conclusion. The data demonstrate that Ras-and c-Myc-dependent signaling events cooperate to regulate the growth and invasiveness of RASFs. Targeting of both c-Raf-1 and c-Myc may constitute an interesting therapeutic approach in RA.Growing evidence suggests that activated synovial fibroblasts (SFs) play a pivotal role in the pathogenesis of rheumatoid arthritis (RA), a systemic disabling disease that primarily affects the joints and results in their progressive destruction (1). Such activated fibroblasts are found predominantly in the synovial lining and appear largely responsible for the progressive destruction of articular cartilage. Apart from an altered morphology (2), changes in the expression of protooncogenes (3) and tumor suppressor genes (4,5) have been demonstrated in RASFs. Among the signaling molecules Supported by grants from the Swiss National Science Foundation (SNSF 32-64142.00) and the Deutsche Forschungsgemeinschaft (DFG Pa 698/1-1, Pa 698/2-1, and Mu 1383/3-3).

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Induction of β3-Integrin Gene Expression by Sustained Activation of the Ras-Regulated Raf–MEK–Extracellular Signal-Regulated Kinase Signaling Pathway

Cited by 118 publications

References 90 publications

Reciprocal regulation of MelCAM and AKT in human melanoma

Reciprocal regulation of MelCAM and AKT in human melanoma

Integrin β3 expression is regulated by let-7a miRNA in malignant melanoma

Cooperation of Ras‐ and c‐Myc–dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in rheumatoid arthritis

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