Regulation of IRF and STAT gene expression by retinoic acid.

Retinoic acid has antiproliferative and differentiative effects on many cell types. However, the molecular mechanisms involved in ATRA (all-trans retinoic acid) -dependent growth inhibition and cell differentiation are poorly understood. On the other hand, several different cytokine specific transcription factors such as signal transducers and activators of transcription (STAT) and interferon regulatory factors (IRF) are known to be instrumental in mediating differentiative, growth regulatory and antiproliferative effects in cells. The IRF family consists of six different proteins, of which IRF-1 has been demonstrated to have antiproliferative and tumor suppressive functions. We have shown that ATRA activates IRF-1 gene expression in several myeloid leukemia cell lines (HL-60, NB4, THP-1, U937), all of which respond to ATRA by growth inhibition. In addition, during ATRA-induced myeloid differentiation, gene expression of STAT1, STAT2, and p48 was upregulated. These proteins are involved in IFN-alpha specific signaling. ATRA-induced expression of IRF and/or STAT transcription factors may be one of the molecular mechanisms mediating growth inhibition by ATRA.