The prodomain of interleukin 1alpha interacts with elements of the RNA processing apparatus and induces apoptosis in malignant cells.
Interleukin 1alpha (IL-1alpha), a 33 kDa precursor, is cleaved releasing the 17 kDa carboxyl-terminal cytokine IL-1alpha to which all of the biological properties of IL-1alpha have been attributed. We investigated the potential independent properties of the remaining 16 kDa IL-1alpha amino-terminal propiece by expression in human tumor and primary human cell lines. The IL-1alpha propiece produced apoptosis in malignant but not normal cell lines. A minimal fragment comprised of amino acids 55-108 was required for apoptosis. Deletion and mutation studies identified an extended nuclear localization sequence required for nuclear localization, induction of apoptosis and concentration of the IL-1alpha propiece in interchromatin granule clusters, concentrations of proteins in the RNA splicing and processing pathways. The IL-1alpha propiece interacted with five known components of the RNA splicing/processing pathway, suggesting that the mechanism of action may involve changes in RNA splicing or processing. Expression of the IL-1alpha propiece caused a shift in the ratio of Bcl-Xl/Bcl-Xs toward the apoptotic direction. Our findings indicate that the IL-1alpha propiece induces apoptosis in a range of tumor cells and likely operates through a mechanism involving the RNA processing apparatus and the alternate splicing of apoptosis regulatory proteins.
Pollock
Allan S
AS
The Department of Medicine, University of California, San Francisco, Northern California Institute for Research and Education, Veterans Administration Medical Center, San Francisco, California 94121, USA. pollock.allan@maelstrom.ucsf.edu
Turck
Johanna
J
Lovett
David H
DH
D000595:Amino Acid Sequence; D017209:Apoptosis; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049452:Green Fluorescent Proteins; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D007375:Interleukin-1; D008164:Luminescent Proteins; D011498:Protein Precursors; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D049452:Green Fluorescent Proteins