Human delta-lactoferrin is a transcription factor that enhances Skp1 (S-phase kinase-associated protein) gene expression.
In: FEBS Journal, Jg. 274 (2007-04-15), Heft 8, S. 2038-2053
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Zugriff:
Delta-lactoferrin is a cytoplasmic lactoferrin isoform that can locate to the nucleus, provoking antiproliferative effects and cell cycle arrest in S phase. Using macroarrays, the expression of genes involved in the G 1 /S transition was examined. Among these, Skp1 showed 2–3-fold increased expression at both the mRNA and protein levels. Skp1 (S-phase kinase-associated protein) belongs to the Skp1/Cullin-1/F-box ubiquitin ligase complex responsible for the ubiquitination of cellular regulators leading to their proteolysis. Skp1 overexpression was also found after delta-lactoferrin transient transfection in other cell lines (HeLa, MDA-MB-231, HEK 293) at comparable levels. Analysis of the Skp1 promoter detected two sequences that were 90% identical to those previously known to interact with lactoferrin, the secretory isoform of delta-lactoferrin (GGCACTGTAC-S1 Skp1 , located at − 1067 bp, and TAGAAGTCAA-S2 Skp1 , at − 646 bp). Both gel shift and chromatin immunoprecipitation assays demonstrated that delta-lactoferrin interacts in vitro and in vivo specifically with these sequences. Reporter gene analysis confirmed that delta-lactoferrin recognizes both sequences within the Skp1 promoter, with a higher activity on S1 Skp1 . Deletion of both sequences totally abolished delta-lactoferrin transcriptional activity, identifying them as delta-lactoferrin-responsive elements. Delta-lactoferrin enters the nucleus via a short bipartite RRSDTSLTWNSVKGKK(417–432) nuclear localization signal sequence, which was demonstrated to be functional using mutants. Our results show that delta-lactoferrin binds to the Skp1 promoter at two different sites, and that these interactions lead to its transcriptional activation. By increasing Skp1 gene expression, delta-lactoferrin may regulate cell cycle progression via control of the proteasomal degradation of S-phase actors. [ABSTRACT FROM AUTHOR]
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Human delta-lactoferrin is a transcription factor that enhances Skp1 (S-phase kinase-associated protein) gene expression.
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Autor/in / Beteiligte Person: | Mariller, Christophe ; Benaïssa, Monique ; Hardivill, Stephan ; Breton, Mathilde ; Pradelle, Guillaume ; Mazurier, Joël ; Pierce, Annick |
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Zeitschrift: | FEBS Journal, Jg. 274 (2007-04-15), Heft 8, S. 2038-2053 |
Veröffentlichung: | 2007 |
Medientyp: | academicJournal |
ISSN: | 1742-464X (print) |
DOI: | 10.1111/j.1742-4658.2007.05747.x |
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