The oncogenic protein BCL-3, a member of the IκB family, was originally identified in a subset of human B-cell chronic lymphocytic leukemias that carry a translocation t(14,19), which results in BCL-3 overexpression. BCL-3 is also overexpressed in many solid tumors, such as in breast cancers and in cylindromas. This IκB protein activates or represses gene transcription through binding with the NF-κB proteins p50 and p52. Furthermore, BCL-3 is K63-linked polyubiquitinated, which leads to its translocation into the nucleus and to its target genes expression. BCL-3 is also K48-linked polyubiquitinated after GSK3 phosphorylation, which leads to its subsequent proteasomal degradation. However, the mechanisms underlying both its polyubiquitination and its ability to repress gene transcription remain poorly understood.
In order to gain more insight into these BCL-3 functions, parallel screenings involving both yeast-two-hybrid experiments and biochemical purifications led to the identification of BCL-3-interacting partners. Those screenings identified CtBP as a molecule required for the ability of BCL-3 to repress gene transcription. CtBP is also required for the stability, for the oncogenic potential and for the ability of BCL-3 to inhibit UV-mediated cell apoptosis in keratinocytes. We also defined the E3 ligase TBLR1 as a key element involved in BCL-3 polyubiquitination and degradation through a GSK3-independent pathway and the proteasome subunit PSMB1 as a protein required for the GSK3-dependent and -independent proteasomal degradation of polyubiquitinated BCL-3. Importantly, all interactions require unique motifs within the amino-terminal domain of BCL-3.
In conclusion, our data define multiple BCL-3-associated proteins that differentially and specifically regulate its function and stability and indicate that a better understanding of the mechanisms underlying the oncogenic properties of this IκB protein could be achieved through similar interactomic studies.
| Identifer | oai:union.ndltd.org:BICfB/oai:ETDULg:ULgetd-10052010-172725 |
| Date | 21 October 2010 |
| Creators | Keutgens, Aurore |
| Contributors | BEYAERT, Rudi, BOURS, Vincent, STRUMAN, Ingrid, PIETTE, Jacques, PEERS, Bernard, NOEL, Agnès, COURTOIS, Gilles, ANGENOT, Luc, CHARIOT, Alain, MERVILLE, Marie-Paule |
| Publisher | Universite de Liege |
| Source Sets | Bibliothèque interuniversitaire de la Communauté française de Belgique |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://bictel.ulg.ac.be/ETD-db/collection/available/ULgetd-10052010-172725/ |
| Rights | restricted, Je certifie avoir complété et signé le contrat BICTEL/e remis par le gestionnaire facultaire. |
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