Role and regulation of the thrombin receptor (PAR-1) in human melanoma

Tellez, Carmen S.; Bar‐Eli, Menashe

doi:10.1038/sj.onc.1206453

Cited by 118 publications

(115 citation statements)

References 97 publications

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“…AP-2 is a well-characterized transcription factor and is believed to play a tumor-suppressor-like role in melanoma progression by regulating genes involved in invasive melanoma (see review; Tellez and Bar-Eli, 2003). Therefore, we asked whether AP-2 expression increased skeletrophin in cultured melanoma cells.…”

Section: Ap-2 Increased Skeletrophin Expression In Melanoma Cellsmentioning

confidence: 99%

A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion

et al. 2006

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Section: Ap-2 Increased Skeletrophin Expression In Melanoma Cellsmentioning

confidence: 99%

A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion

et al. 2006

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“…PAR-1 expression has been detected in human melanoma (12), colon adenocarcinoma (13), pancreatic cancer (14), and SCCHN (15,16). However, the role of PAR-1 in metastasis has not been clearly defined in current publications.…”

Section: Introductionmentioning

confidence: 99%

Correlation of Protease-Activated Receptor-1 With Differentiation Markers in Squamous Cell Carcinoma of the Head and Neck and Its Implication in Lymph Node Metastasis

Zhang

Hunt²,

Landsittel

et al. 2004

Clinical Cancer Research

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Purpose: Protease-activated receptor-1 (PAR-1) is a Gprotein-coupled receptor that contributes to multiple signal transduction pathways. Although the functions of PAR-1 in many normal cells, such as platelets and astrocytes, have been well studied, its roles in cancer progression and metastasis have not been fully elucidated, and studies to date appear contradictory.Experimental Design: To clarify the function of PAR-1 in metastasis of squamous cell carcinoma of the head and neck (SCCHN), we examined PAR-1 expression in clinical specimens by immunohistochemistry and in SCCHN cell lines by immunoblotting. Furthermore, par-1 cDNA-transfected SCCHN cell lines were also used to verify PAR-1-mediated pathway.Results: The metastatic tumors showed a lower percentage of PAR-1-positive cells (46%) and lower levels of PAR-1 expression (median weight index ‫؍‬ 10) than node negative primary tumors (80% and median weight index ‫؍‬ 60, respectively). In addition, expression level of PAR-1 positively correlated with levels of keratinocyte differentiation markers keratin-1, -10, and -11. Additional studies using sense and antisense par-1 cDNA-transfected SCCHN cell lines illustrated that the presence of PAR-1 was required for the expression of involucrin, a keratinocyte differentiation marker. PAR-1 expression also contributes to activation of the mitogen-activated protein kinase (MAPK) pathway. Blocking MAPK activation by a mitogen-activated protein/ extracellular signal-regulated kinase inhibitor, not by a phosphatidylinositol 3 -kinase inhibitor, reduced level of involucrin, suggesting that regulation of involucrin by PAR-1 is partially through the MAPK signaling pathway.Conclusions: Our study suggests that PAR-1 signaling induces differentiation markers in SCCHN cells, and its expression is conversely correlated with cervical lymph node metastasis.

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“…AP2-Alpha has been cited as a tumor suppressor, 38 and combined with the down regulation of CDX, it may point to the mechanism by which corticosteroids suppress cellular proliferation. PAX-4 is normally associated with the differentiation of beta islet cells in the pancreas.…”

Section: Discussionmentioning

confidence: 99%

Context Specific Transcription Factor Prediction

et al. 2007

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Abstract-One of the goals of systems biology is the identification of regulatory mechanisms that govern an organism's response to external stimuli. Transcription factors have been hypothesized as a major contributor to an organism's response to various outside stimuli, and a great deal of work has been done to predict the set of transcription factors which regulate a given gene. Most of the current methods seek to identify possible binding sites from genomic sequence. Initial attempts at predicting transcription factors from genomic sequences suffered from the problem of false positives. Making the problem more difficult, it has also been shown that while predicted binding sites might be false positives, they can be shown to bind to their corresponding sequences in vitro. One method for rectifying this is through the use of phylogenetic analysis in which only regions which show high evolutionary conservation are analyzed. However such an approach may be too stringent because of the level of degeneracy shown in transcription factor binding site position weight matrices. Due to the degeneracy, there may be only a few bases that need to be conserved across species. Therefore, while a sequence may not show a high level of evolutionary conservation, these sequences may still show high affinity for the same transcription factor. In predicting transcription factor binding we explore the notion that ''Coexpression implies co-regulation'' [Allocco et al. BMC Bioinformatics 5:18, 2004]. With multiple genes requiring similar transcription factors binding sites, there exists a basis for eliminating false positives. This method allows for the selection of transcription factors binding sites that are active under a given experimental paradigm, thereby allowing us to indirectly incorporate the effects of chromosome and recognition site presentation upon transcription factor binding prediction. Rather than having to rationalize that a few transcription factors binding sites are over-represented in a cluster of genes, one can show that a few transcription factors are active in the cluster of genes that have been grouped together. Although the method focuses on predicting experiment-specific transcription factor binding sites, it is possible that if such a methodology were used in an iterative process where different experiments were analyzed, one could obtain a comprehensive set of transcription factors binding sites which regulate the various dynamic responses shown by biological systems under a variety of conditions hence building a more comprehensive model of transcriptional regulation.

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Role and regulation of the thrombin receptor (PAR-1) in human melanoma

Cited by 118 publications

References 97 publications

A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion

A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion

Correlation of Protease-Activated Receptor-1 With Differentiation Markers in Squamous Cell Carcinoma of the Head and Neck and Its Implication in Lymph Node Metastasis

Context Specific Transcription Factor Prediction

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