Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC

Abstract

Key words: adenomatous polyposis coli; ␤-catenin; loss of heterozygosity; ICAT; mutation; skin tumor Cutaneous malignant melanomas (CMMs) have shown a marked increase in both incidence and mortality over the past decades. 1 The genetic alterations associated with the development and progression of these tumors are still poorly understood. Cytogenetic and molecular genetic studies have implicated a number of chromosomal and genetic changes in melanoma pathogenesis. 2,3 The genes known to be aberrant in variable subsets of malignant melanomas include tumor-suppressor genes, such as CDKN2A and PTEN, as well as protooncogenes, such as CDK4, NRAS and MYCC. 2-4 A previous study showed that melanoma cell lines frequently carry mutations in the ␤-catenin gene (CTNNB1). 5 The ␤-catenin protein is a central component of the Wnt (wingless) signal-transduction pathway, which plays an important role in development and tumorigenesis. 6 -8 The Wnt signal is transduced through cell membrane-associated receptors of the frizzled family and stabilizes ␤-catenin, which then enters the cell nucleus and forms a complex with members of the Tcf/Lef-1 family of transcription factors. 7,8 Activation of Tcf/Lef-1 by binding to ␤-catenin induces the transcription of various target genes, including protooncogenes such as MYCC and CCND1. 9,10 Within the cell nucleus, the activity of the ␤-catenin-Tcf/Lef-1 complex can be inhibited by the protein Icat (inhibitor of ␤-catenin and Tcf-4), which blocks the interaction between ␤-catenin and Tcf-4 and thereby antagonizes Wnt signaling. 11 In addition, the level of ␤-catenin in the cell is tightly regulated by a multiprotein complex composed of the APC tumor-suppressor protein, axin and Gsk-3␤. 6 -8 In the absence of Wnt signal, this complex promotes the phosphorylation of serine and threonine residues in the aminoterminal region of ␤-catenin by Gsk-3␤. Phosphorylated ␤-catenin can be bound by the F-box and WD40 domain-containing protein Btrc, also known as ␤-Trcp, 12 and is thereby targeted for degradation via the ubiquitin/proteasome pathway. [13][14][15] Oncogenic activation of ␤-catenin by amino acid substitutions or deletions affecting its N-terminal degradation box has been demonstrated in various human tumors, including melanoma cell lines, 5 as well as a small fraction of primary melanomas. 16,17 Individual melanoma cell lines with APC mutations have also been reported. 5 The BTRC and ICAT gene loci map to the long arm of chromosome 10 (10q24.3) and the short arm of chromosome 1 (1p36.2), respectively. 11,18 Both regions are frequently affected by LOH in melanomas. 2,19 -22 Furthermore, a familial melanoma gene locus has been linked to 1p36. 23 Thus, in addition to CTNNB1 and APC, the BTRC and ICAT genes are interesting candidates for melanoma-associated tumor-suppressor genes. To better define the role of alterations in Wnt signaling pathway genes in the pathogenesis of melanomas, we determined the expression of ␤-catenin in a panel of sporadic melanomas from 37 patients and analyzed the...

E-Cadherin Is Required for Caveolin-1-Mediated Down-Regulation of the Inhibitor of Apoptosis Protein Survivin via Reduced β-Catenin-Tcf/Lef-Dependent Transcription

“…Interestingly, high levels of ␤-catenin have been observed in malignant melanomas. Furthermore, activating mutations in the ␤-catenin gene (CTNNB1), as well as genetic and epigenetic alterations of the APC gene, occur in malignant melanomas and are associated with melanoma progression (26,48,62). Thus, as in colon cancer, aberrant Wnt signaling is relevant to the genesis and progression of melanomas.…”

β-Catenin Inhibitor ICAT Modulates the Invasive Motility of Melanoma Cells

“…One of the regulators of this balance might be ICAT, a small acidic protein that sterically competes with members of the TCF/LEF family for binding to b-catenin (6, 7). Although no mutations in the ICAT/CTNNBIP1 gene have been identified in human melanoma samples (13,37,41), the ability of ICAT to regulate b-catenin transcriptional activity may modulate the clinical outcome of patients depending on its level of expression.…”

“…Variable ICAT expression has been detected in metastatic and nonmetastatic human melanoma samples (13,14). However, whether ICAT plays a role in melanoma progression and/or metastasis formation is still unknown.…”

β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development

“…The frequency of activating mutations in the ␤-catenin gene is higher in melanoma cell lines than in tumors (Rubinfeld et al 1997;Rimm et al 1999;Demunter et al 2002;Pollock and Hayward 2002;Reifenberger et al 2002). We performed similar experiments on independent melanomas and melanoma cell lines (data Please note that six out of seven N-Ras mutated melanoma expressing a high level of ␤-catenin produced a low level of p16.…”