Abstract
The oncogenic protein BCL-3 activates or represses gene transcription through binding with the NF-kappaB proteins p50 and p52 and is degraded through a phospho- and GSK3-dependent pathway. However, the mechanisms underlying its degradation remain poorly understood. Yeast two-hybrid analysis led to the identification of the proteasome subunit PSMB1 as a BCL-3-associated protein. The binding of BCL-3 to PSMB1 is required for its degradation through the proteasome. Indeed, PSMB1-depleted cells are defective in degrading polyubiquitinated BCL-3. The N-terminal part of BCL-3 includes lysines 13 and 26 required for the Lys(48)-linked polyubiquitination of BCL-3. Moreover, the E3 ligase FBW7, known to polyubiquitinate a variety of substrates phosphorylated by GSK3, is dispensable for BCL-3 degradation. Thus, our data defined a unique motif of BCL-3 that is needed for its recruitment to the proteasome and identified PSMB1 as a key protein required for the proteasome-mediated degradation of a nuclear and oncogenic IkappaB protein.
Highlights
Tutive NF-B activation seen in most solid and hematological malignancies [8]
The N-terminal domain was required for the nuclear localization of BCL-3, its C-terminal domain was dispensable as a mutant that lacks the entire C-terminal domain downstream of the ankyrin repeats (BCL-3 ⌬C) remained largely nuclear (Fig. 1B)
Whereas the first 30 N-terminal amino acids were required for the nuclear localization of BCL-3, they were dispensable for the interaction with p50 or with p52 as the BCL-3 ⌬N30 mutant still bound both NF-B proteins, as judged by co-immunoprecipitation analysis (Fig. 1C, top panels, lane 5)
Summary
Tutive NF-B activation seen in most solid and hematological malignancies [8]. BCL-3 overexpression has been reported in multiple myelomas and subtypes of lymphomas, even in the absence of any t(14; 19) chromosomal translocation [9,10,11,12]. Multiple mechanisms that include chromosomal rearrangements or mutations of BCL-3-associated proteins trigger BCL-3 overexpression in the nucleus, a key event in BCL-3-mediated oncogenesis. This IB protein has been defined formally as an oncoprotein based on the ability of BCL-3-expressing NIH3T3 cells to form foci and induce tumor growth in nude mice and because bcl-3 transgenic mice developed lymphoproliferative disorders [18, 19]. To gain more insight on BCL-3 functions, we conducted yeast two-hybrid analysis and defined the proteasome subunit PSMB1 as a BCL-3-interacting protein that binds an unique sequence within the N-terminal domain of this oncoprotein This interaction is required for BCL-3 degradation, as evidenced by the stabilization of BCL-3 in PSMB1-depleted cells. Our data defined PSMB1 as a key protein required for the proteasome-dependent degradation of a nuclear IB protein
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
