Signal transducer and activator of transcription 3 is a transcriptional factor regulating the gene expression of SALL4

FASEB J. 2009 May;23(5):1405-14. doi: 10.1096/fj.08-117721. Epub 2009 Jan 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Consensus Sequence
  • Down-Regulation
  • Humans
  • Mutagenesis, Site-Directed
  • Promoter Regions, Genetic
  • STAT3 Transcription Factor / physiology*
  • Tetracycline / pharmacology
  • Transcription Factors / genetics*

Substances

  • SALL4 protein, human
  • STAT3 Transcription Factor
  • Transcription Factors
  • Tetracycline