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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3849-3855.
Prepublished online as a Blood First Edition Paper on February 13, 2007January 16, 2007; DOI 10.1182/blood-2006-11-056879.
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Submitted November 9, 2006
Accepted December 18, 2006
Nur77 converts phenotype of Bcl-B, an anti-apoptotic
protein expressed in plasma cells and myeloma
Frederic Luciano, Maryla Krajewska, Paulina Ortiz-Rubio, Stan Krajewski, Dayong Zhai, Benjamin Faustin, Jean-Marie Bruey, Beatrice Bailly-Maitre, Alan Lichtenstein, Siva Kumar Kolluri, Arnold C Satterthwait, Xiao-Kun Zhang, and John C Reed*
Burnham Institute for Medical Research, La Jolla, CA
Veterans Administration for Greater Los Angeles Healthcare System, Los Angeles, CA
* Corresponding author; email: reedoffice{at}burnham.org.
Defects in apoptosis mechanisms play important roles in malignancy and autoimmunity. Orphan nuclear receptor Nur77/TR3 has been demonstrated to bind anti-apoptotic protein Bcl-2 and convert it from a cytoprotective to a cytodestructive protein, representing a phenotypic conversion mechanism. Of the six anti-apoptotic 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-XL, Mcl-1 or Bcl-W. Nur77 converts the phenotype of Bcl-B from anti- to pro-apoptotic. Bcl-B is prominently expressed in plasma cells and multiple myeloma. Endogenous Bcl-B associates with endogenous Nur77 in RPMI8226 myeloma cells, where RNA interference experiments demonstrated dependence on Bcl-B for Nur77-induced apoptosis. Furthermore, a Nur77-mimicking peptide killed RPMI8226 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.
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