Autocrine interleukin-1beta production in leukemia: evidence for the involvement of mutated RAS. Cancer Res 1999 Jun 15;59(12):2971-80
Date
06/26/1999Pubmed ID
10383163Scopus ID
2-s2.0-0033563322 (requires institutional sign-in at Scopus site) 50 CitationsAbstract
Interleukin (IL)-1beta is constitutively expressed in many leukemias and operates as an autocrine growth factor. To study the cellular basis for this aberrant production, we analyzed two cell lines, B1 (acute lymphoblastic leukemia) and W1 (juvenile chronic myelogenous leukemia), which express high levels of IL-1beta and have mutations in the K-RAS and N-RAS genes, respectively. Electromobility shift assays demonstrated transcription factor binding at multiple IL-1beta promoter elements [nuclear factor (NF)-IL6/CREB, NFB1, NFkappaB, and NF-IL6], consistent with the activation of an upstream signaling pathway. To determine whether activated Ras was involved, two structurally distinct classes of farnesyltransferase (FTase) inhibitors (the monoterpenes and a peptidomimetic) and an adenoviral vector expressing antisense targeted to K-RAS were used to specifically interfere with Ras function and/or expression. Treatment with the FTase inhibitors resulted in a concentration-dependent decrease in both NF-IL6/CREB binding to the IL-1beta promoter and IL-1beta protein levels, without a significant change in total cellular protein levels. Furthermore, exposure of the B1 cells to antisense against K-RAS resulted in an approximately 50% reduction in both p21Ras and IL-1beta protein levels. Growth suppression was observed after FTase inhibitor or antisense exposure, an effect that was partially reversible by the addition of recombinant IL-1beta to the cultures. Our observations suggest that mutated RAS genes may mediate autocrine IL-1beta production in some leukemias by stimulating signal transduction pathways that activate the IL-1beta promoter.
Author List
Beaupre DM, Talpaz M, Marini FC 3rd, Cristiano RJ, Roth JA, Estrov Z, Albitar M, Freedman MH, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Alkyl and Aryl TransferasesAnti-Inflammatory Agents
Autocrine Communication
Blotting, Southern
CCAAT-Enhancer-Binding Proteins
Cell Division
Cyclic AMP Response Element-Binding Protein
Cycloheximide
DNA-Binding Proteins
Dexamethasone
Enzyme Inhibitors
Farnesyltranstransferase
Gene Amplification
Gene Expression
Gene Rearrangement
Genes, ras
Humans
Infant
Interleukin-1
Leukemia
Mutation
Nuclear Proteins
Oligonucleotides, Antisense
Promoter Regions, Genetic
Protein Synthesis Inhibitors
RNA, Messenger
Signal Transduction
Terpenes
Transcription Factors
Tumor Cells, Cultured
