Abstract
Expression of the chemokine MGSA/GRO is upregulated as melanocytes progress to melanoma cells. We demonstrate that constitutive and cytokine induced MGSA/GRO alpha expression requires multiple DNA regulatory regions between positions -143 to -62. We have previously shown that the NF-kappa B element at -83 to -65 is essential for basal and cytokine induced MGSA/GRO alpha promoter activity in the Hs294T melanoma and normal retinal pigment epithelial (RPE) cells, respectively. Here, we have determined that the Sp1 binding element located approximately 42 base pairs upstream from the NF-kappa B element binds Sp1 and Sp3 constitutively and this element is necessary for basal MGSA/GRO alpha promoter activity. We demonstrate that the high mobility group proteins HMGI(Y) recognize the AT-rich motif nested within the NF-kappa B element in the MGSA/GRO alpha promoter. Loss of either NF-kappa B or HMGI(Y) complex binding by selected point mutations in the NF-kappa B element results in decreased basal and cytokine induced MGSA/GRO alpha promoter activity. Thus, these results indicate that transcriptional regulation of the chemokine MGSA/GRO alpha requires at least three transcription factors: Sp1, NF-kappa B and HMGI(Y).
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Base Sequence
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Cells, Cultured
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Chemokine CXCL1
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Chemokines, CXC*
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Chemotactic Factors / genetics*
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DNA / metabolism
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DNA Footprinting
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DNA, Neoplasm / metabolism
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / pharmacology
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Enhancer Elements, Genetic / genetics
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Gene Expression Regulation / drug effects
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Gene Expression Regulation, Neoplastic / drug effects*
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Growth Substances / genetics*
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HMGA1a Protein
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High Mobility Group Proteins / metabolism
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High Mobility Group Proteins / pharmacology*
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Humans
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Intercellular Signaling Peptides and Proteins*
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Melanoma
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Molecular Sequence Data
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NF-kappa B / metabolism
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NF-kappa B / pharmacology*
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Neoplasm Proteins / genetics*
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Pigment Epithelium of Eye / cytology
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Promoter Regions, Genetic / genetics
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Sp1 Transcription Factor / metabolism
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Sp1 Transcription Factor / pharmacology*
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Sp3 Transcription Factor
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Transcription Factors / metabolism
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Transcription Factors / pharmacology
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Transcription, Genetic / drug effects*
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Tumor Cells, Cultured
Substances
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CXCL1 protein, human
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Chemokine CXCL1
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Chemokines, CXC
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Chemotactic Factors
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DNA, Neoplasm
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DNA-Binding Proteins
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Growth Substances
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High Mobility Group Proteins
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Intercellular Signaling Peptides and Proteins
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NF-kappa B
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Neoplasm Proteins
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SP3 protein, human
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Sp1 Transcription Factor
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Transcription Factors
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HMGA1a Protein
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Sp3 Transcription Factor
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DNA