Regulation of CD26/DPPIV gene expression by interferons and retinoic acid in tumor B cells

Interferons (IFNs alpha, beta and gamma) and all trans retinoic acid (RA) h ave the ability to activate genes with GAS sites. We have found that the pr omoter of CD26/dipeptidylpeptidase IV (DPPIV) contains a consensus GAS site TTCnnnGAA located at bp-35 to -27, and computer analysis confirmed this se quence to be a putative Stat binding site. Consistent with this finding, we show that IFNs and RA rapidly enhanced CD26 gene and protein expression in chronic B lymphocytic leukemia (B-CLL) cells. Immunoblot analyses revealed that unstimulated B-CLL cells expressed detectable levels of serine/tyrosi ne-phosphorylated Stat1 alpha, and RA and IFN-gamma treatment led to increa sed levels of tyrosine phosphorylation of Stat1 alpha and its nuclear accum ulation. As shown by electrophoretic mobility shift assay, RA and IFN-gamma increased the binding of a nuclear protein to the GAS-CD26 element. Shift- Western blotting identified Stat1 alpha as the GAS-CD26 binding factor. Aug mented levels of CD26 protein in malignant B cells cultured with IFNs or RA coincided with the enhancement of DPPIV activity. Taken together, our resu lts are in favor of the IFN-/RA-mediated upregulation of CD26/DPPIV in B-CL L through the signaling pathway involving Stat1 alpha and the GAS response element of CD26 promoter.