Signal transducer and activator of transcription 3 is a transcriptional factor regulating the gene expression of SALL4.
Both signal transducer and activator of transcription 3 (STAT3) and SALL4 are important in maintaining the pluripotent and self-renewal state of embryonic stem cells. We hypothesized that STAT3, a latent transcriptional factor, may regulate the gene expression of SALL4. In support of this hypothesis, DNA sequence analysis of the SALL4 gene promoter revealed four putative STAT3-binding sites. Using a SALL4-luciferase reporter gene assay, we found that modulation of the STAT3 activity significantly up-regulated the luciferase activity. By chromatin immunoprecipitation, the segment of the SALL4 promoter showing the highest affinity to STAT3 was localized to -366 to -163, in which there was only one putative STAT3 binding site starting at -199. Site-directed mutagenesis of all four putative STAT3-binding sites in the SALL4 promoter significantly reduced its responsiveness to STAT3, although the most dramatic effect was seen at the binding site starting at -199. We further tested the functional relationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALL4 expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negative construct resulted in a significant decrease in the expression of SALL4. To conclude, our data suggest that STAT3 and SALL4 probably cooperate in both physiological and pathological states.
Bard
J Dien
JD
Department of Laboratory Medicine and Pathology, University of Alberta, 11560 University Ave., Edmonton, AB, Canada T6G 1Z2.
Gelebart
P
P
Amin
H M
HM
Young
L C
LC
Ma
Y
Y
Lai
R
R
D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D016384:Consensus Sequence; D015536:Down-Regulation; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000502:physiology*; D013752:Tetracycline / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*
C472575:SALL4 protein, human; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D013752:Tetracycline