Stat1 is induced and activated by all-trans retinoic acid in acute promyelocytic leukemia cells.
Treatment of freshly isolated acute promyelocytic leukemia (APL) cells and the myelogenous leukemia cell lines, NB4, HL-60, and U937, with all-trans retinoic acid (ATRA) results in a remarkable elevation in the amounts of Stat1 alpha and Stat2 proteins. Stat1 alpha protein levels are augmented by ATRA as a consequence of elevated amounts of the corresponding transcripts. The retinoid increases the levels of nuclear complexes that are capable of binding to interferon (IFN)-regulated consensus sequences and contain Stat1 and/or Stat2 proteins, and causes a rapid and long-lasting elevation in Stat1 alpha tyrosine phosphorylation. Transient transfection experiments show that ATRA enhances the transactivating properties of Stat1 alpha observed on an appropriate reporter gene, in the presence of the RAR alpha retinoic acid receptor, but not in the presence of the PML-RAR protein. Treatment of NB4 cells with ATRA is associated with a remarkable upregulation of the two IFN-responsive genes IFN-responsive factor 1 and 2'-5' oligoadenylate synthetase, as well as with an augmentation in the levels of IFN alpha secretion. Our data show that ATRA is capable of modulating the amounts and the state of activation of some of the components of the IFN intracellular signaling pathways. They also suggest that the retinoid can bypass IFN/IFN-receptor interactions and induce the expression of IFN-regulated genes.
Gianni
M
M
Molecular Biology Unit, Centro Catullo e Daniela Borgomainerio, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Terao
M
M
Fortino
I
I
LiCalzi
M
M
Viggiano
V
V
Barbui
T
T
Rambaldi
A
A
Garattini
E
E
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D007372:Interferons / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000187:drug effects; D017471:Receptors, Interferon / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D050832:Interferon-Stimulated Gene Factor 3; D009687:Nuclear Proteins; D017471:Receptors, Interferon; D014157:Transcription Factors; C079868:gamma interferon activation factor; D014212:Tretinoin; D007372:Interferons; D011505:Protein-Tyrosine Kinases; D015088:2',5'-Oligoadenylate Synthetase