Stat1 Involvement in Retinoic Acid Induced Differentiation of Myeloid Cells

摘要

All-trans retinoic acid (ATRA) is a potent cyto-differentiating agent that induces terminal differentiation and cell-cycle arrest of several myeloid cell lines in vitro, including the human monoblast cell line U-937. This function of ATRA, to promote differentiation of immature cells, has been used successfully in the clinical treatment of acute promyelocytic leukemia. Recent reports have shown that ATRA induces the expression of several interferon-regulated genes, including Signal Transducer and Activator of Transcription (STAT)1. Statl is important for transducing signals from interferons and many interleukines, and is phosphorylated on both a conserved tyrosine and serine residue upon activation. To investigate the role of Statl activation in ATRA induced differentiation of U-937 cells, we established cell lines constitutively expressing phosphorylation defective (Y701F or S727F) or wildtype Statl and tested their response to ATRA. We found that clones expressing either Statl(Y701F) or Statl(S727F) were unable to terminally differentiate in response to ATRA. Also, ATRA induced cell-cycle arrest was inhibited in clones expressing phosphorylation defective Statl, leading to a continued proliferation and DNA synthesis after induction. Our results indicate that activation of Statl plays a central role in ATRA induced terminal differentiation and cell-cycle arrest of U-937 cells.