Receptor to nucleus signaling by prolactin and interleukin 2 via activation of latent DNA-binding factors.
The mechanism of action of prolactin (PRL), a lactogenic and immunoregulatory hormone, has remained undetermined despite its critical role in development. This study identifies a DNA-binding factor induced by PRL that appears to mediate a signal from the cell surface receptor to specific gene expression in the nucleus. PRL stimulates the proliferation of Nb2 T-lymphoma cells and activates transcription of the interferon-regulatory factor 1 (IRF-1) gene. Within minutes of PRL stimulation, a PRL-induced factor (PRLIF) is activated and binds to a target site in the promoter of the IRF-1 gene. The PRLIF-binding site contains an inverted GAAA repeat that is also functional in the hormone-responsive beta-casein gene. The PRL-receptor complex signals tyrosine phosphorylation of JAK2, a nonreceptor tyrosine kinase, which may lead to activation of PRLIF. T-cell proliferation and transcriptional activation of the IRF-1 gene is also induced by the cytokine interleukin 2 (IL-2). This report demonstrates the rapid activation of an IL-2 nuclear-activated factor that recognizes the same GAAA inverted repeat in the IRF-1 promoter. PRLIF and IL-2 nuclear-activated factor are newly identified factors that appear to serve fundamental roles in the signal transduction pathways of PRL and IL-2, respectively, leading to the transcriptional regulation of responsive genes.
Gilmour
K C
KC
Department of Pathology, State University of New York at Stony Brook 11794-8691.
Reich
N C
NC
D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D050856:Interferon Regulatory Factor-1; D007376:Interleukin-2 / Q000502:physiology*; D053614:Janus Kinase 2; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics; D010766:Phosphorylation; D011388:Prolactin / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D007376:Interleukin-2; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D011388:Prolactin; D004247:DNA; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2