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Titolo:
ANALYSES OF BETA-THALASSEMIA MUTANT-DNA INTERACTIONS WITH ERYTHROID KRUPPEL-LIKE FACTOR (EKLF), AN ERYTHROID CELL-SPECIFIC TRANSCRIPTION FACTOR
Autore:
FENG WC; SOUTHWOOD CM; BIEKER JJ;
Indirizzi:
CUNY MT SINAI SCH MED,BROOKDALE CTR MOLEC BIOL,BOX 1126,1 GUSTAVE L LEVY PL NEW YORK NY 10029 CUNY MT SINAI SCH MED,BROOKDALE CTR MOLEC BIOL,BOX 1126,1 GUSTAVE L LEVY PL NEW YORK NY 10029 CUNY MT SINAI SCH MED,DEPT PHYSIOL & BIOPHYS NEW YORK NY 10029 CUNY MT SINAI SCH MED,DEPT BIOCHEM NEW YORK NY 10029
Titolo Testata:
The Journal of biological chemistry
fascicolo: 2, volume: 269, anno: 1994,
pagine: 1493 - 1500
SICI:
0021-9258(1994)269:2<1493:AOBMIW>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
PORPHOBILINOGEN DEAMINASE GENE; MURINE ERYTHROLEUKEMIA-CELLS; ZINC-BINDING DOMAINS; GLOBIN GENE; FACTOR-IIIA; FINGER PROTEIN; CONTROL REGION; PROMOTER; SEQUENCE; RECOGNITION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
66
Recensione:
Indirizzi per estratti:
Citazione:
W.C. Feng et al., "ANALYSES OF BETA-THALASSEMIA MUTANT-DNA INTERACTIONS WITH ERYTHROID KRUPPEL-LIKE FACTOR (EKLF), AN ERYTHROID CELL-SPECIFIC TRANSCRIPTION FACTOR", The Journal of biological chemistry, 269(2), 1994, pp. 1493-1500

Abstract

We describe functional tests and molecular modeling of erythroid Kruppel-like factor (EKLF) interactions with its DNA binding site. EKLF, azinc finger-containing, erythroid-specific transcription factor, binds and transactivates from the CACCC element, an evolutionarily conserved DNA sequenee present within a large number of erythroid-specific promoters and enhancers. This DNA binding element is the site of naturally occurring point mutations that give rise to beta-thalassemia. We have directly tested whether CAC site point mutations (including two of the beta-thalassemia mutants) affect EKLF transactivation and DNA binding function. In vivo analyses demonstrate that EKLF is unable to transactivate a reporter plasmid that contains these mutations. In vitro analyses reveal a 40-100-fold decrease in binding affinity for these sites that accounts for the in vivo observations. The homology between the three EKLF and Zif268 zinc fingers and their conserved sequence-specific contaets to their target site allowed us to formulate a molecular model of the EKLF/CAC site complex, based primarily on energy minimization/refinement of the Zif268/DNA co-crystal structure. These modelssuggest that both specific and nonspecific hydrogen bonding play a critical role in the ability of EKLF to prefer binding to its cognate site. Analysis of sequence-specific contacts by EKLF to its target site within the beta-globin promoter verified the residues predicted to be important by the functional and modeling data. Together these results demonstrate that EKLF displays a strong discriminatory ability among potential DNA target sites consistent with the beta-thalassemia data. They also suggest that lack of EKLF binding to these sites may play a determining role in its phenotype, and they strengthen the evidence in favor of EKLFs proposed role in erythroid-specific transcriptional activation through the CACCC elements.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/09/20 alle ore 13:14:31