| Molekulare Profilanalyse von kutanen Melanomen und funktionelle Charakterisierung von ASK/Dbf4 | |
Abstract/OtherAbstract
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The molecular and genetic events that contribute to the development and progression of malignant melanoma are only partly understood. To identify novel determinants for tumor development and progression, oligonucleotide microarraybased comparison of gene expression profiles of a series of nevi primary cutaneous melanomas, cutaneous melanoma metastases and melanoma cell lines with normal human melanocytes (NHM) as calibrator, was performed. Based on this data, molecular changes between benign nevi and primary cutaneous melanoma were distinct and discernible. In contrast between primary cutaneous melanoma and metastasis the data revealed no absolute distinction. Presumably a considerable overlap of expressed genes between cutaneous melanoma and metastasis as seen in this study reflects the close biological relationship between them by describing gradual changes. Since qRT-PCR based multi-gene prediction models was un attempted in melanoma, this study was the first to generate a multi-gene signature containing 4 genes namely ASK/Dbf4, Tpr, c-MET and MCAM/MUC18 that were able to differentiate nevi from melanoma. This study then further focused on functional characterization of the role of ASK/Dbf4, one of the components in this 4-gene signature. In keeping with its expected role as a cyclin-like regulatory subunit of mammalian Cdc7, the data suggested that upregulated ASK is localized to the nucleus and binds to human Cdc7 to form Cdc7-ASK/Dbf4 complexes in melanoma cells. Subsequently, this study also demonstrated that ASK has an essential function in melanoma cell growth by showing that siRNA-mediated specific depletion of ASK retarded cell survival and proliferation. Furthermore, the current study also explained that ASK/Dbf4 is a transcriptional target of the important cell cycle regulator E2F1 in melanoma and that it is a melanoma modulated gene refractory to melanoma risk factor UVB and hence its expression may not be an early event in melanomagenesis. Thus in summary, this study identified and characterized, a novel cell survival gene in melanoma, namely ASK/Dbf4. |
Authors
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Nambiar, Sandeep |
Contributors
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Hengge, Ulrich, Hegemann, J. H. |
Publication Detail
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Publisher : - Type : Dissertation Format : Text |
Date Detail
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2007-06-22 |
Subject
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57 |
Coverage
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- |
Relation
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- |
Source
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- |
Copyright Information
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free |
Other Details
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Languages : ger |
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