Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma.
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.
Luciano
Frederic
F
Burnham Institute for Medical Research, 10901 Torrey Pines Road, La Jolla, CA 92037, USA.
Krajewska
Maryla
M
Ortiz-Rubio
Paulina
P
Krajewski
Stan
S
Zhai
Dayong
D
Faustin
Benjamin
B
Bruey
Jean-Marie
JM
Bailly-Maitre
Beatrice
B
Lichtenstein
Alan
A
Kolluri
Siva Kumar
SK
Satterthwait
Arnold C
AC
Zhang
Xiao-Kun
XK
Reed
John C
JC
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000187:drug effects; D019556:COS Cells; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D009101:Multiple Myeloma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010455:Peptides / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology / Q000378:metabolism; D011987:Receptors, Steroid / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; C117144:BCL2-like 10 protein; D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors