Document Detail

PMA up-regulates the transcription of Axl by AP-1 transcription factor binding to TRE sequences via the MAPK cascade in leukaemia cells.
MedLine Citation:
PMID:  20977427     Owner:  NLM     Status:  In-Data-Review    
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.
Giridhar Mudduluru; Jörg H Leupold; Philipp Stroebel; Heike Allgayer
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Publication Detail:
Type:  Journal Article    
Journal Detail:
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:
Created Date:  2010-12-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8108529     Medline TA:  Biol Cell     Country:  England    
Other Details:
Languages:  eng     Pagination:  21-33     Citation Subset:  IM    
*Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors, DKFZ and University of Heidelberg, Mannheim 68167, Germany.
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