Dimerization co-factor of hepatocyte nuclear factor 1/pterin-4 alpha-carbinolamine dehydratase is necessary for pigmentation in Xenopus and overexpressed in primary human melanoma lesions
ABSTRACT Dimerization co-factor of hepatocyte nuclear factor 1 (HNF1)/pterin-4alpha-carbinolamine dehydratase (DCoH/PCD) is both a positive co-factor of the HNF1 homeobox transcription factors and thus involved in gene regulation as well as an enzyme catalyzing the regeneration of tetrahydrobiopterin. Dysfunction of DCoH/PCD is associated with the human disorders hyperphenylalaninemia and vitiligo. In Xenopus, overexpression of the protein during development induces ectopic pigmentation. In this study loss of function experiments using DCoH/PCD-specific antibodies demonstrated that the protein is also absolutely necessary for pigment cell formation in Xenopus. In normal human skin DCoH/PCD protein is weakly expressed in the basal layer of the epidermis that consists of keratinocytes and melanocytes. Whereas only 4 of 25 benign nevi reacted with DCoH/PCD-specific antibodies, high protein levels were detectable in melanoma cell lines and 13 of 15 primary malignant melanoma lesions. The comparison with the commonly used melanoma markers S100 and HMB45 demonstrated that DCoH/PCD has an overlapping but distinct expression pattern in melanoma lesions. In addition to human colon cancer, this is the second report about the overexpression of DCoH/PCD in human tumor cells indicating that the protein might be involved in cancerogenesis.
SourceAvailable from: Beat Thöny
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ABSTRACT: Melanin production is the primary mechanism protecting human skin against the UV light-induced damage. The polymeric compound melanin is synthesized within melanocytes in the specialized subcellular organelles, termed melanosomes, which are then transferred to surrounding keratinocytes. The genes for melanin synthesis and deposition are coordinately expressed in melanocytes. The transcription factor MITF, which has been reported to activate more than 25 genes in pigment cells, has emerged as an essential regulator not only for melanocyte development, proliferation and survival, but also for the expression of enzymes and structural proteins ensuring the production of melanin. MITF is a transcriptional activator of several genes which encode melanosome-localized proteins involved both in melanin synthesis and in melanosome biogenesis and transport, including genes whose mutations are associated with human oculocutaneous and ocular forms of albinism. Here, we outline the mechanisms of transcriptional regulation of genes associated with the biosynthesis of melanin in melanocytes and melanoma cells. MITF is crucial in this process, while several other factors seem to have only an auxiliary role to play under specific circumstances.Experimental Dermatology 02/2010; 19(7):617-27. DOI:10.1111/j.1600-0625.2009.01053.x · 4.12 Impact Factor
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ABSTRACT: Osteosarcoma (OS) is a rare bone neoplasm that affects mainly adolescents. It is associated with poor prognosis in case of metastases formation. The search for metastasis predicting markers is therefore imperative to optimize treatment strategies for patients at risk and important for the search of new drugs for the treatment of this devastating disease. Here, we have analyzed by microarray the differential gene expression in four human and two mouse OS cell line systems consisting of parental cell lines with low metastatic potential and derivatives thereof with increased metastatic potential. Using two osteoblastic cell line systems, the most common OS phenotype, we have identified forty-eight common genes that are differentially expressed in metastatic cell lines compared to parental cells. The identified subset of metastasis relevant genes in osteoblastic OS overlapped only minimally with differentially expressed genes in the other four preosteoblast or nonosteoblastic cell line systems. The results imply an OS phenotype specific expression pattern of metastasis regulating proteins and form a basis for further investigation of gene expression profiles in patients' samples combined with survival analysis with the aim to optimize treatment strategies to develop new drugs and to consequently improve the survival of patients with the most common form of osteoblastic OS.Sarcoma 11/2012; 2012:937506. DOI:10.1155/2012/937506