Abstract
Defects in apoptosis mechanisms play important roles in malignancy and autoimmunity. Orphan nuclear receptor Nur77/TR3 has been demonstrated to bind antiapoptotic protein Bcl-2 and convert it from a cytoprotective to a cytodestructive protein, representing a phenotypic conversion mechanism. Of the 6 antiapoptotic human Bcl-2 family members, we found that Nur77/TR3 binds strongest to Bcl-B, showing selective reactivity with Bcl-B, Bcl-2, and Bfl-1 but not Bcl-X(L), Mcl-1, or Bcl-W. Nur77 converts the phenotype of Bcl-B from antiapoptotic to proapoptotic. Bcl-B is prominently expressed in plasma cells and multiple myeloma. Endogenous Bcl-B associates with endogenous Nur77 in RPMI 8226 myeloma cells, where RNA interference experiments demonstrated dependence on Bcl-B for Nur77-induced apoptosis. Furthermore, a Nur77-mimicking peptide killed RPMI 8226 myeloma cells through a Bcl-B-dependent mechanism. Because Bcl-B is abundantly expressed in plasma cells and some myelomas, these findings raise the possibility of exploiting the Nur77/Bcl-B mechanism for apoptosis for eradication of autoimmune plasma cells or myeloma.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis Regulatory Proteins / immunology
-
Apoptosis Regulatory Proteins / metabolism
-
Autoimmunity / drug effects
-
COS Cells
-
Cell Death / drug effects
-
Cell Death / immunology
-
Chlorocebus aethiops
-
DNA-Binding Proteins / immunology
-
DNA-Binding Proteins / metabolism
-
DNA-Binding Proteins / pharmacology*
-
Gene Expression Regulation, Neoplastic* / immunology
-
HeLa Cells
-
Humans
-
Multiple Myeloma / immunology
-
Multiple Myeloma / metabolism*
-
Multiple Myeloma / pathology
-
Nuclear Receptor Subfamily 4, Group A, Member 1
-
Peptides / immunology
-
Peptides / metabolism
-
Peptides / pharmacology*
-
Plasma Cells / immunology
-
Plasma Cells / metabolism*
-
Plasma Cells / pathology
-
Proto-Oncogene Proteins c-bcl-2 / immunology
-
Proto-Oncogene Proteins c-bcl-2 / metabolism*
-
Receptors, Cytoplasmic and Nuclear / immunology
-
Receptors, Cytoplasmic and Nuclear / metabolism
-
Receptors, Steroid / immunology
-
Receptors, Steroid / metabolism
-
Transcription Factors / immunology
-
Transcription Factors / metabolism
-
Transcription Factors / pharmacology*
Substances
-
Apoptosis Regulatory Proteins
-
BCL2-like 10 protein
-
DNA-Binding Proteins
-
NR4A1 protein, human
-
Nuclear Receptor Subfamily 4, Group A, Member 1
-
Peptides
-
Proto-Oncogene Proteins c-bcl-2
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Steroid
-
Transcription Factors