title: Interferon regulatory factor-1 binds c-Cbl, enhances mitogen activated protein kinase signaling and promotes retinoic acid-induced differentiation of HL-60 human myelo-monoblastic leukemia cells.
abstract: All-trans retinoic acid (RA) and interferons (IFNs) have efficacy in treating certain leukemias and lymphomas, respectively, motivating interest in their mechanism of action to improve therapy. Both RA and IFNs induce interferon regulatory factor-1 (IRF-1). We find that in HL-60 myeloblastic leukemia cells which undergo mitogen activated protien kinase (MAPK)-dependent myeloid differentiation in response to RA, IRF-1 propels differentiation. RA induces MAPK-dependent expression of IRF-1. IRF-1 binds c-Cbl, a MAPK related adaptor. Ectopic IRF-1 expression causes CD38 expression and activation of the Raf/MEK/ERK axis, and enhances RA-induced differentiation by augmenting CD38, CD11b, respiratory burst and G0 arrest. Ectopic IRF-1 expression also decreases the activity of aldehyde dehydrogenase 1, a stem cell marker, and enhances RA-induced ALDH1 down-regulation. Interestingly, expression of aryl hydrocarbon receptor (AhR), which is RA-induced and known to down-regulate Oct4 and drive RA-induced differentiation, also enhances IRF-1 expression. The data are consistent with a model whereby IRF-1 acts downstream of RA and AhR to enhance Raf/MEK/ERK activation and propel differentiation.
authors: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Miaoqing
authors: M
authors: Shen
authors: Rodica P
authors: RP
authors: Bunaciu
authors: Johanna
authors: J
authors: Congleton
authors: Holly A
authors: HA
authors: Jensen
authors: Lavanya G
authors: LG
authors: Sayam
authors: Jeffrey D
authors: JD
authors: Varner
authors: Andrew
authors: A
authors: Yen
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D007948:Leukemia, Monocytic, Acute / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D011485:Protein Binding; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D050856:Interferon Regulatory Factor-1; D018336:Receptors, Aryl Hydrocarbon; D014212:Tretinoin; D050721:Proto-Oncogene Proteins c-cbl; D051997:ADP-ribosyl Cyclase 1