title: Cross-talk between Dopachrome Tautomerase and Caveolin-1 Is Melanoma Cell Phenotype-specific and Potentially Involved in Tumor Progression.
abstract: l-Dopachrome tautomerase (l-DCT), also called tyrosinase-related protein-2 (TRP-2), is a melanoma antigen overexpressed in most chemo-/radiotherapeutic stress-resistant tumor clones, and caveolin-1 (CAV1) is a main regulator of numerous signaling processes. A structural and functional relationship between DCT and CAV1 is first presented here in two human amelanotic melanoma cell lines, derived from vertical growth phase (MelJuSo) and metastatic (SKMel28) melanomas. DCT co-localizes at the plasma membrane with CAV1 and Cavin-1, another molecular marker for caveolae in both cell phenotypes. Our novel structural model proposed for the DCT-CAV1 complex, in addition to co-immunoprecipitation and mass spectrometry data, indicates a possible direct interaction between DCT and CAV1. The CAV1 control on DCT gene expression, DCT post-translational processing, and subcellular distribution is cell phenotype-dependent. DCT is a modulator of CAV1 stability and supramolecular assembly in both cell phenotypes. During autocrine stimulation, the expressions of DCT and CAV1 are oppositely regulated; DCT increases while CAV1 decreases. Sub-confluent MelJuSo clones DCT(high)/CAV1(low) are proliferating and acquire fibroblast-like morphology, forming massive, confluent clusters as demonstrated by immunofluorescent staining and TissueFAXS quantitative image cytometry analysis. CAV1 down-regulation directly contributes to the expansion of MelJuSo DCT(high) subtype. CAV1 involved in the perpetuation of cell phenotype-overexpressing anti-stress DCT molecule supports the concept that CAV1 functions as a tumor suppressor in early stages of melanoma. DCT is a regulator of the CAV1-associated structures and is possibly a new molecular player in CAV1-mediated processes in melanoma.
authors.affiliation: Department of Protein Folding, Institute of Biochemistry of the Romanian Academy, 060031 Bucharest, Romania.
authors.forename: Ioana L
authors.initials: IL
authors.lastname: Popa
authors.affiliation: Department of Bioinformatics and Structural Biochemistry, Institute of Biochemistry of the Romanian Academy, 060031 Bucharest, Romania.
authors.forename: Adina L
authors.initials: AL
authors.lastname: Milac
authors.affiliation: Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, 060031 Bucharest, Romania.
authors.forename: Livia E
authors.initials: LE
authors.lastname: Sima
authors.affiliation: Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, 060031 Bucharest, Romania.
authors.forename: Petruta R
authors.initials: PR
authors.lastname: Alexandru
authors.affiliation: Department of Bioinformatics and Structural Biochemistry, Institute of Biochemistry of the Romanian Academy, 060031 Bucharest, Romania.
authors.forename: Florin
authors.initials: F
authors.lastname: Pastrama
authors.affiliation: Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, 060031 Bucharest, Romania.
authors.forename: Cristian V A
authors.initials: CVA
authors.lastname: Munteanu
authors.affiliation: Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, 060031 Bucharest, Romania. Electronic address: gnegroiu@biochim.ro.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Negroiu
mesh_terms: D015153:Blotting, Western; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010641:Phenotype; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051242:Caveolin 1; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase
keywords: antigen processing; caveolin; epithelial-mesenchymal transition (EMT); melanoma; structural model