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

J. Dien Bard^*,1, P. Gelebart^*,1, H. M. Amin, L. C. Young^*, Y. Ma and R. Lai^*,2

^* Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada;

Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA; and

Department of Hematopathology, Nevada Cancer Center, Las Vegas, Nevada, USA

² Correspondence: Dept. of Laboratory Medicine and Pathology, University of Alberta, 11560 University Ave., Edmonton, AB, Canada T6G 1Z2. E-mail: raymondl{at}cancerboard.ab.ca

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.—Dien Bard, J., Gelebart, P., Amin, H. M., Young, L. C., Ma, Y., Lai, R. Signal transducer and activator of transcription 3 is a transcriptional factor regulating the gene expression of SALL4.

Key Words: cell signaling • luciferase assay • chromatin immunoprecipitation