The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism.
Expression of survivin, a member of the inhibitor of apoptosis protein family, is elevated in human cancers and considered as a new therapeutic target. Mechanism upregulating survivin expression in tumour cells is poorly understood. In this study, we show that breast cancer patients harbouring a polymorphism G235A in the survivin promoter present a higher level of survivin expression. This polymorphism creates a binding site for the transcription factor GATA-1 inducing a second GATA-1-binding site in survivin promoter. At the mRNA level, GATA-1 was present in breast carcinomas and adjacent normal tissues, whereas the protein was only detected in carcinomas by western blot and immunohistochemistry. Transfection of wild-type and different constitutively active GATA-1 mutants (serine 26, 178 or 310) showed that only phospho-serine 26 GATA-1 was able to increase survivin expression. This increase was higher in G235A than in G235G cell lines. Phospho-serine 26 GATA-1 bound directly survivin promoter, with a stronger interaction in G235A than in G235G polymorphism indicating that both GATA-1-binding sites are functional. These data identify GATA-1 as a key feature in tumour aggressiveness by enhancing survivin expression and delineate its targeting as a possible new therapeutic strategy in breast carcinomas.
Boidot
R
R
Centre Georges-François Leclerc, Molecular Genetics Laboratory, Dijon, France.
Végran
F
F
Jacob
D
D
Chevrier
S
S
Cadouot
M
M
Feron
O
O
Solary
E
E
Lizard-Nacol
S
S
D001665:Binding Sites; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D050982:GATA1 Transcription Factor / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D000077022:Survivin; D015854:Up-Regulation
C107489:BIRC5 protein, human; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin