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) have the ability to activate genes with GAS sites. We have found that the promoter of CD26/dipeptidylpeptidase IV (DPPIV) contains a consensus GAS site TTCnnnGAA located at bp-35 to -27, and computer analysis confirmed this sequence 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/tyrosine-phosphorylated Stat1alpha, and RA and IFN-gamma treatment led to increased levels of tyrosine phosphorylation of Stat1alpha and its nuclear accumulation. 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 Stat1alpha as the GAS-CD26 binding factor. Augmented levels of CD26 protein in malignant B cells cultured with IFNs or RA coincided with the enhancement of DPPIV activity. Taken together, our results are in favor of the IFN-/RA-mediated upregulation of CD26/DPPIV in B-CLL through the signaling pathway involving Stat1alpha and the GAS response element of CD26 promoter.
Bauvois
B
B
Unité 365 INSERM, Institut Curie, 75231 Paris cedex 05, France.
Djavaheri-Mergny
M
M
Rouillard
D
D
Dumont
J
J
Wietzerbin
J
J
D002469:Cell Separation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis* / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000502:physiology*; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; C079868:gamma interferon activation factor; D014443:Tyrosine; D014212:Tretinoin; D007371:Interferon-gamma; D007372:Interferons; D018819:Dipeptidyl Peptidase 4