Molecular mechanisms underlying SHP-1 gene expression.

SHP-1, a protein-tyrosine phosphatase with two src-homology 2 domains, is expressed predominantly in hematopoietic and epithelial cells and has been implicated in numerous signaling pathways as a negative regulator. Two promoters direct the expression of human and murine SHP-1, and two types of transcripts (I) and (II) SHP-1, are initiated from each of these promoters. The cDNA sequences of (I)SHP-1 and (II)SHP-1 are identical except in the 5' untranslated region and in the first few coding nucleotides. In this report, we show that promoter usage is similar in mouse and human hematopoietic cells, but different in epithelial cells. In human epithelial cells, only (I)SHP-1 transcripts were expressed. In addition, 4beta-phorbol 12-myristate 13-acetate up-regulates human (I)SHP-1 transcript expression in SKOV3 cells (an ovarian cancer cell line). Indirect evidence suggests that nuclear factor-kappaB might play a role in this induction. We also show that a 12-bp repeat in the distal SHP-1 promoter, which directs (I)SHP-1 expression, is of functional relevance as deletion of one copy of this E-box-containing 12-bp repeat resulted in a significant decrease in promoter activity. Electrophoretic mobility shift assays and supershift experiments showed that the upstream stimulatory factors USF1 and USF2 hetero-dimerize and interact with this 12 bp repeat. Our results suggest that USFs which have antiproliferative functions might regulate the expression of SHP-1, which itself is predominantly a negative growth regulator.