Informatic and genomic analysis of melanocyte cDNA libraries as a resource for the study of melanocyte development and function.
ABSTRACT As part of the RIKEN mouse encyclopedia project, two cDNA libraries were prepared from melanocyte-derived cell lines, using techniques of full-length clone selection and subtraction/normalization to enrich for rare transcripts. End sequencing showed that these libraries display over 83% complete coding sequence at the 5' end and 96-97% complete coding sequence at the 3' end. Evaluation of the libraries, derived from B16F10Y tumor cells and melan-c cells, revealed that they contain clones for a majority of the genes previously demonstrated to function in melanocyte biology. Analysis of genomic locations for transcripts revealed that the distribution of melanocyte genes is non-random throughout the genome. Three genomic regions identified that showed significant clustering of melanocyte-expressed genes contain one or more genes previously shown to regulate melanocyte development or function. A catalog of genes expressed in these libraries is presented, providing a valuable resource of cDNA clones and sequence information that can be used for identification of new genes important for melanocyte development, function, and disease.
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ABSTRACT: Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma.Pigment Cell & Melanoma Research 08/2009; 22(6):773-84. · 5.84 Impact Factor
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ABSTRACT: Several parallels between stem cell biology and tumour behaviour have been discovered in recent times. Such commonality is apparent in the unlimited capacity for cell division together with the lack of a differentiated phenotype in embryonic and adult stem cells, traits shared with tumour cells. Differentiation is a tightly regulated process that is mediated by the actions of multiple transcription factor families. The POU domain-containing family of transcription factors contains multiple mammalian members divided into six classes, which can be expressed broadly or in a cell-specific manner, and which are regulators of cell fate decisions of many different lineages. Target gene regulation can occur via a POU factor acting alone, or in combination with other POU proteins, ubiquitous co-activators or co-repressors, or other lineage restricted transcription factors. Aberrant levels of POU proteins have been found in several malignancies, including melanoma, connecting the otherwise developmentally restricted gene regulatory functions of POU transcription factors to the critical determinants of malignant transformation. Here, we focus on the role of the BRN2 (POU3F2/N-Oct-3) transcription factor in the melanocytic lineage where it may co-ordinate normal developmental cues that can be re-activated in melanoma. Recent studies have shown BRN2 to be responsive to MAPK pathway activation and to modulate the levels of MITF so as to suppress the differentiated melanocytic phenotype and to enhance tumour metastasis.Pigment Cell & Melanoma Research 11/2008; 21(6):611 - 626. · 5.84 Impact Factor
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ABSTRACT: Extensive studies of the biology of the pigment-producing cell (melanocyte) have resulted in a wealth of knowledge regarding the genetics and developmental mechanisms governing skin and hair pigmentation. The ease of identification of altered pigment phenotypes, particularly in mouse coat color mutants, facilitated early use of the pigmentary system in mammalian genetics and development. In addition to the large collection of developmental genetics data, melanocytes are of interest because their malignancy results in melanoma, a highly aggressive and frequently fatal cancer that is increasing in Caucasian populations worldwide. The genetic programs regulating melanocyte development, function, and malignancy are highly complex and only partially understood. Current research in melanocyte development and pigmentation is revealing new genes important in these processes and additional functions for previously known individual components. A detailed understanding of all the components involved in melanocyte development and function, including interactions with neighboring cells and response to environmental stimuli, will be necessary to fully comprehend this complex system. The inherent characteristics of pigmentation biology as well as the resources available to researchers in the pigment cell community make melanocytes an ideal cell type for analysis using systems biology approaches. In this review, the study of melanocyte development and pigmentation is considered as a candidate for systems biology-based analyses.Wiley Interdisciplinary Reviews Systems Biology and Medicine 01/2009; 1(3):359-71. · 3.68 Impact Factor