| PMA up-regulates the transcription of Axl by AP-1 transcription factor binding to TRE sequences via the MAPK cascade in leukaemia cells. | |
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MedLine Citation:
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PMID: 20977427 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Background. Axl is a receptor tyrosine kinase promoting anti-apoptosis, invasion and mitogenesis, and is highly expressed in different solid cancers. Axl basal transcriptional activity is driven by Sp1/Sp3, and overexpression of MZF-1 (myeloid zinc-finger 1) induces Axl transcription and gene expression. Furthermore, Axl expression is epigenetically controlled by CpG hypermethylation; however, little is known about inducible Axl gene expression and Axl regulation in haematopoetic malignancies. Results. In the present study, we studied Axl transcriptional regulation under PMA-stimulated conditions in leukaemia cells. Luciferase analysis with sequential 5'-deletion constructs revealed that the -660/-580 region of the Axl promoter is indispensable for induced promoter activity under PMA stimulation. This region includes AP-1 (activator protein 1)/CREB [CRE (cAMP-response-element)-binding protein] motifs, five times partially overlapping TGCGTG repeats and multiple GT repeats. Mutational, supershift and ChIP (chromatin immunoprecipitation) analysis determined that AP-1 family members bind to AP-1 motifs and to the 5 × TGCGTG overlapping repeats, thus transactivating Axl promoter activity. Furthermore, specific inhibitors of PKC (protein kinase C), ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 reduced Axl expression. Additionally, mithramycin treatment abolished constitutive and PMA-induced Axl expression. Conclusions. Taken together the results of the present study suggest that PMA-induced Axl gene expression in leukaemia cells is mediated by AP-1 motifs and 5 × TGCGTG repeats within the promoter region -660/-580, and through the PKC/ERK1/2/AP-1 or PKC/p-38/AP-1 signalling axis. |
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Authors:
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Giridhar Mudduluru; Jörg H Leupold; Philipp Stroebel; Heike Allgayer |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Biology of the cell / under the auspices of the European Cell Biology Organization Volume: 103 ISSN: 1768-322X ISO Abbreviation: Biol. Cell Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-14 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8108529 Medline TA: Biol Cell Country: England |
Other Details:
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Languages: eng Pagination: 21-33 Citation Subset: IM |
Affiliation:
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*Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors, DKFZ and University of Heidelberg, Mannheim 68167, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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