Role and regulation of PAR-1 in melanoma progression

Carmen Tellez, Menashe Bar-Eli

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

To determine treatment strategies and predict the clinical outcome of patients with melanoma it is important to understand the etiology of this disease. Recently, there has been some insight into the molecular basis of melanoma, including identification of a few of the regulatory factors and genes involved in this disease. For instance, the transcription factor, activator protein (AP)-2α, plays a tumor suppressor- like role in melanoma progression by regulating genes involved in tumor growth and metastasis. Previously, we have shown that the progression of human melanoma to the metastatic phenotype is associated with loss of AP-2 expression and deregulation of target genes, such as MUC18/MCAM, c-KIT, and MMP-2. This chapter focuses on the expression of the thrombin receptor (protease-activated receptor [PAR]-1) in human melanoma and its regulation by AP-2 and specificity protein (Sp)-1. We demonstrate that the metastatic potential of human melanoma cells correlates with overexpression of PAR-1. We also provide evidence that an inverse correlation exists between the expression of AP-2 and the expression of PAR-1 in human melanoma cells. The regulatory region of the PAR-1 gene contains multiple AP-2 consensus elements overlapping multiple Sp1 consensus elements. Our analysis of the highly overlapping AP-2 and Sp1 binding elements (complex 1, bp -365 to -329) within the regulatory region demonstrates that AP-2 and Sp1 bind to this region in a mutually exclusive manner to promote repression or activation, respectively. We propose that loss of AP-2 results in increased expression of the thrombin receptor, which subsequently contributes to the metastatic phenotype of melanoma by upregulating the expression of adhesion molecules, proteases, and angiogenic molecules.

Original languageEnglish (US)
Title of host publicationFrom Melanocytes to Melanoma
Subtitle of host publicationThe Progression to Malignancy
PublisherHumana Press
Pages489-502
Number of pages14
ISBN (Print)1588294595, 9781588294593
DOIs
StatePublished - 2006

Keywords

  • AP-2
  • Melanoma
  • angiogenesis
  • gene expression
  • gene regulation
  • metastasis
  • thrombin receptor
  • transcription factor

ASJC Scopus subject areas

  • General Medicine

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