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With previous indication of the Group VIA phospholipase A2 (iPLA2β) enzyme regulating ER-stress induced apoptosis in β-cells by regulating the anti-apoptotic protein Bcl-xL via alternative splicing, our lab postulated iPLA2β to be utilizing a similar mechanism to regulate apoptosis in mice lung. Our previous lab work has shown implications of lung function compromise in iPLA2β-/- mice, and we speculated the cause to be due altered lung architecture stemming from the attenuation of apoptosis. The western blot analysis in this study suggested that iPLA2β is involved in the regulation of Bcl-xL, but the mRNA ratios of the splice variants suggested that alternative splicing is not the mechanism iPLA2β is utilizing for the regulation in our animal models. Additionally, the observation and assessment of the lung morphology of the iPLA2β-/- and wild type mice suggested that iPLA2β does not play an integral role in lung morphology.

L’homéostasie calcique est régulée par de nombreux canaux ioniques, parmi lesquels des canaux intracellulaires perméables au Ca2+, comme l’IP3R. Récemment, la protéine Bcl-2 a été montré comme régulant l’activité de ce canal ionique. Cependant, les acteurs moléculaires précis de cette interaction ne sont pas très bien établis. Ici nous montrons grâce à une nouvelle technique que l’IP3R est inhibé par le domaine BH4 de Bcl-2 et que ce domaine est nécessaire et suffisant pour inhiber son activité. De plus, la liaison de l’ABT-199 dans la poche hydrophobe de Bcl-2 conduit à un changement de structure du domaine BH4. Le niveau d’expression des différentes isoformes d’IP3R ainsi que des protéines Bcl-2 et Bcl-xL ont été étudié dans différentes lignées cancéreuses prostatiques. De manière intéressante, l’expression du récepteur à l’IP3 de type 3 (IP3R3) est augmentée en fonction de l’agressivité des lignées cancéreuses prostatiques. De plus, nous pouvons observer un effet important de l’IP3R3 sur la migration et l’invasion des lignées humaines de cancer de la prostate. Globalement, ces données montrent que l’IP3R3 participe à l’augmentation du potentiel métastatique des cellules cancéreuses prostatiques. Par conséquent, l’IP3R3 peut être un marqueur diagnostic intéressant ainsi qu’une cible thérapeutique, notamment pour les stades avancés de cancer de la prostate. / Calcium homeostasis is regulated by various ion channels, among which intracellular Ca2+-permeable channels, such as IP3R. Lately, Bcl-2 protein have been shown to regulate this ion channel activity. However, the study of the functional properties of IP3R in interaction with Bcl-2 is not a straightforward procedure and the molecular players implicated in that interaction are still not well established. Here, we show with the use of a new electrophysiological method, that the IP3R is inhibited by Bcl-2 via its BH4 domain and that the BH4 domain of Bcl-2 can inhibit by itself the single channel activity of the IP3R. Moreover, the binding of the ABT-199 in the hydrophobic groove of Bcl-2 leads to a tail-flip structural change in BH4 domain. We also studied the expression level of different IP3R isoforms as well as Bcl-2 and Bcl-xL protein in different prostate cancer cell lines. Interestingly, IP3R type 3 (IP3R3) expression is increased according the aggressiveness of prostate cancer cell lines. Indeed, IP3R3 was expressed preferentially in highly aggressive prostate cancer cell lines. Moreover, we can observe an significantly important effect of the IP3R3 on migration and invasion properties of human prostate cancer cell lines. Our study also revealed that IP3R3 was not involved in viability, proliferation. Overall, these data provide evidence on IP3R3 contribution to the increased metastatic potential of human prostate cancer cells. Therefore, IP3R3 could provide new perspective molecular target for the disease suppression, in particular at its advances stages.

Adenomas hipofisários são tumores benignos, de crescimento lento, originados no interior da sela túrcica e constituem de 10% a 15% dos tumores intracranianos, Os adenomas clinicamente não funcionantes (ACNF), correspondem aproximadamente um terço dos adenomas em geral. Por não apresentarem síndrome clínica hormonal são geralmente diagnosticados devido a sintomas neurológicos ou oftalmológicos, como macroadenomas, com grandes dimensões, invasão de estruturas circunvizinhas e hipopituitarismo. A cirurgia é o tratamento de escolha para estes tumores e apesar de ser eficaz na resolução do quadro compressivo, a possibilidade de cura cirúrgica é reduzida principalmente em tumores invasivos. Seu acompanhamento pós-operatório é efetuado por exame de imagem, preferencialmente ressonância magnética, devido à indisponibilidade de marcadores séricos. Nesta pesquisa avaliou-se a relação da expressão dos genes relacionados à apoptose, Bcl-2, Bax e Caspase-3 e sua relação com o comportamento dos ACNF. Na Divisão de Neurocirurgia Funcional do Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo foram operados 119 doentes com tumores hipofisários, de 28/05/08 à 07/04/09, 50 deles com ACNF, 30 deles foram estudados. A ressonância magnética da região selar pré-operatória possibilitou a medida dos três maiores diâmetros do tumor, ou seja, antero-posterior (AP), crânio-caudal (CC), látero-lateral (LL) e avaliar a invasão do seios cavernoso e esfenoidal. O tamanho dos tumores foi avaliado pela soma dos três diâmetros, pelo maior diâmetro e pelo cálculo do volume, efetuado pela fórmula AP x CC x LL x 0,5. No intraoperatório foram avaliados, a consistência e invasão tumoral. A análise histológica por hematoxilina-eosina, foi efetuada em todos os tumores, assim como a análise imuno-histoquímica (IHQ) dos hormônios hipofisários, Ki-67, p53 e Bcl-2. Foi realizada a análise molecular dos genes Bcl-2, Bax e Caspase-3 por RT-PCR. Dados demográficos: 17 do sexo masculino, 13 do sexo feminino, mediana da idade foi de 54,5 anos e mediana da duração dos sintomas de 31 meses. Todos apresentavam macroadenoma, 87% deles com perda visual, 53% com cefaléia, 17% com outras alterações neurológicas e um assintomático diagnosticado incidentalmente. Avaliação hormonal, disponível em 26 doentes, confirmou deficiência em 92% deles, com mais de dois eixos acometidos em 50% dos casos. A mediana do volume dos tumores foi de 11,6 cm3, do maior diâmetro de 3,8cm e da soma dos três diâmetros de 8,6cm, observou estreita correlação significativa estatisticamente entre as três medidas. Quarenta porcento dos tumores eram gigantes (diâmetro maior ou igual a 4 cm). Consistência amolecida e invasão tumoral foram observadas em 87% e 67% dos tumores, respectivamente. Todos doentes foram operados pela via transesfenoidal, exceto um operado por craniotomia pterional. Complicações cirúrgicas ocorreram em cinco pacientes, três com fistula liquórica, dois com meningite e dois óbitos. A análise histológica confirmou o diagnóstico de adenoma hipofisário em todos os casos. A IHQ foi negativa para todos hormônios em 18 e positiva em 12 tumores (TSH, FSH, LH, GH ou ACTH). A IHQ para proteína P-53 foi negativa em todos os casos. A IHQ para KI-67 revelou ausência da proteína em 11, positividade em menos de 3% das células em 15 e em mais de 3% em 4 tumores. A IHQ para Bcl-2 foi positiva em apenas três pacientes. A análise molecular dos genes Bcl-2, Bax e Caspase-3 revelou expressão muito inferior nos tumores em relação à observada para um pool de hipófise normal. Observou-se correlação positiva estatisticamente significante entre os três genes porém não foi observada correlação entre os níveis destes três genes e nenhum fator de prognóstico tumoral estudado, quais sejam, idade, positividade para hormônios na IHQ, tamanho ou invasão tumoral / Pituitary adenomas are benign, slow-growing tumors that arise in the sella turcica and account for 10% to 15% of all intracranial tumors. Non-functioning pituitary adenomas (NFPA) account for around one third of all pituitary adenomas. NFPA do not clinically present as hormonal syndromes and are generally diagnosed as macroadenomas due to marked neurological and ophthalmologic symptoms and invasion of surrounding structures, beside hypopituitarism. Surgery is the gold standard to treat these tumors. It effectively relieves compressive symptoms but cure is uncommon. Despite benign in nature, NFPA usually show aggressive behavior. There are no hormonal markers and the follow-up usually is made only by magnetic resonance imaging. Apoptosis-related genes, Bcl-2, Bax, and caspase-3, were here studied in NFPA to assess their role as potential markers of tumor behavior. Out of 119 patients with pituitary adenomas treated by surgery, 30 patients (17 men, 13 women, median age 54.5 years old) harboring NFPA who underwent surgery in the Department of Functional Neurosurgery at Hospital das Clínicas Psychiatric Institute, University of S. Paulo Medical School, from August 2008 to July 2009, were studied. Information on gender, age, pituitary function, symptoms and their length was collected. Tumor dimensions were measured using magnetic resonance imaging of the sella turcica. The tumor volume was calculated by the following equation: anterior-posterior diameter x cranial-caudal diameter x lateral-lateral diameter x 0.5. Intra-operative information such as tumor invasion and consistence was recorded. Histological examination by hematoxylin-eosin staining and immunohistochemistry analysis of pituitary hormones, Ki-67, p53, and Bcl-2 were performed. The molecular analysis of Bcl-2, Bax, and caspase-3 genes was performed by real-time polymerase chain reaction (RT-PCR) in all tumor specimens collected during surgery and compared to a poll of normal pituitary gland. All patients had macroadenomas diagnosed due to visual loss (87%), headache (53%) and other neurological symptoms (17%) and one case was incidentally found. Hormonal deficits were seen in 92% of 26 cases; more than two axes were involved in half of these patients. There was found good correlation between tumor volume, largest diameter and the sum of the 3 diameters, and tumor volume was used to assess the correlations with other parameters. The median volume was 11.6 cm3. Giant tumors (4 cm) were diagnosed in 40% of the patients. Soft tumors and tumor invasion were observed in 87% and 67% of cases, respectively. A transsphenoidal approach was used in all patients, except one who had pterional craniotomy. Five patients presented post-operative complications: three had CSF leakage, two meningitis and two died. The histological examination confirmed pituitary adenoma in all cases, 18 of them were null cell and 12 showed a positive immunohistochemistry analysis for one or more hormones, mainly TSH. Immunohistochemistry analysis results for p-53 was negative in all cases; for Ki-67 was negative in 11, positive in less than 3% of the cells in 15 and positive in more than 3% of the cells in 4 cases; and for Bcl-2 was positive only in three patients. Bcl-2, Bax and caspase-3 molecular analysis revealed very low expression compared to normal pituitary values. There was found a positive correlation between these three genes but no correlation between them and age, tumor volume or invasion. The Bcl-2, Bax, and caspase-3 gene analysis by RT-PCR in NFPA did not evidence their potential as markers of tumor behavior

Chiu Kin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 100-116). / Abstract also in Chinese. / TABLE OF CONTENTS --- p.I / ACKNOWLEDGEMENTS --- p.V / LIST OF FIGURES --- p.VI / LIST OF ABBREVIATIONS --- p.VIII / ABSTRACT --- p.1 / Chapter 1. --- INTRODUCTION --- p.5 / Chapter 2. --- LITERATURE REVIEW --- p.7 / Chapter 2.1 --- RETINAL ISCHEMIA --- p.7 / Chapter 2.1.1 --- INDUCTION OF RETINAL ISCHEMIA --- p.7 / Chapter 2.1.2 --- MECHANISMS OF RETINAL ISCHEMIA/REPERFUSION DAMAGE --- p.8 / Chapter 2.1.2.1. --- Free radical --- p.8 / Chapter 2.1.2.2 --- Excitotoxicity --- p.9 / Chapter 2.1.3 --- APOPTOSIS IN RETINAL ISCHEMIA/REPERFUSION INJURY --- p.10 / Chapter 2.2 --- RETINAL DYSTROPHIC ROYAL COLLEGE OF SURGEONS (RCS) RAT --- p.15 / Chapter 2.3 --- BCL-2 FAMILY MEMBERS --- p.16 / Chapter 2.3.1 --- FAMILY MEMBERS AND THEIR INTERACTIONS --- p.16 / Chapter 2.3.2 --- SUBCELLULAR LOCALIZATION --- p.18 / Chapter 2.3.3 --- PHYSICAL STRUCTURE AND PORE FORMATION --- p.19 / Chapter 2.3.4 --- BIOLOGICAL EFFECTS OF BCL-2 --- p.20 / Chapter 3. --- OBJECTIVES --- p.24 / Chapter 4. --- MATERIALS AND METHODS --- p.27 / Chapter 4.1. --- RETINAL ISCHEMIA AND REPERFUSION INDUCED LOSS OF INNER RETINAL ELEMENTS --- p.27 / Chapter 4.1.1. --- TISSUE RESPONSES IN THE RAT RETINAS AFTER TRANSIENT ELEVATED INTRAOCULAR PRESSURE INDUCED RETINAL ISCHEMIA/REPERFUSION INSULT --- p.27 / Chapter 4.1.1.1. --- Induction of retinal ischemia/reperfusion insult with transient elevated intraocular pressure (IOP) --- p.27 / Chapter 4.1.1.2. --- Animal experiments --- p.28 / Chapter 4.1.1.3. --- Histopathology and measurement of inner retinal thickness (IRT) --- p.28 / Chapter 4.1.1.4. --- Flat preparation of the retinas and retinal ganglion cell counts (RGCCs) --- p.29 / Chapter 4.1.2. --- INTERNUCLEOSOMAL DNA FRAGMENTATION AND IN SITU NICKED DNA DETECTIONS AT DIFFERENT TIME AFTER REPERFUSION IN THE RAT RETINAS --- p.30 / Chapter 4.1.2.1. --- Enzyme-linked immunosorbent assay (ELISA) of mono- and oligonucleosomes --- p.30 / Chapter 4.1.2.2. --- In-situ terminal deoxynucleotidyl transferase (TdT)-mediated biotin- dUTP nicked end labelling (TUNEL) --- p.31 / Chapter 4.1.3. --- "IMMUNOHISTOCHEMISTRY OF BCL-2, BAX AND P53" --- p.32 / Chapter 4.1.4. --- "DOUBLE LABELLING OF BCL-2, BAX AND TUNEL" --- p.33 / Chapter 4.1.5. --- IN-SITU REVERSE TRANSCRIPTASE - POLYMERASE CHAIN REACTION OF BCL-2 AND BAX --- p.34 / Chapter 4.1.5.1. --- Primers design and specificity test --- p.34 / Chapter 4.1.5.2. --- In-situ RT-PCR --- p.36 / Chapter 4.2. --- LOSS OF INNER RETINAL ELEMENTS IN THE RETINAL DYSTROPHIC ROYAL COLLEGE OF SURGEONS (RCS) RATS --- p.38 / Chapter 4.2.1. --- HISTOPATHOLOGY --- p.38 / Chapter 4.2.2 --- MORPHOMETRY OF CELLS IN THE RETINAL GANGLION CELL LAYER (RGCL) AND THE INNER NUCLEAR LAYER (INL) --- p.39 / Chapter 4.2.3. --- IMMUNOHISTOCHEMISTRY OF BCL-2 AND BAX --- p.39 / Chapter 5. --- RESULTS --- p.40 / Chapter 5.1. --- RETINAL ISCHEMIA AND REPERFUSION INDUCED LOSS OF INNER RETINAL ELEMENTS --- p.40 / Chapter 5.1.1. --- TISSUE RESPONSES IN THE RAT RETINAS AFTER TRANSIENT ELEVATED INTRAOCULAR PRESSURE INDUCED ISCHEMIA/ REPERFUSION INSULT --- p.40 / Chapter 5.1.1.1. --- Histopathology --- p.40 / Chapter 5.1.1.2. --- Morphometry of inner retinal thickness --- p.40 / Chapter 5.1.1.3. --- Retinal ganglion cell counts (RGCCs) --- p.41 / Chapter 5.1.2. --- INTERNUCLEOSOMAL DNA FRAGMENTATION AND IN SITU NICKED DNA DETECTION AT DIFFERENT TIME AFTER REPERFUSION IN THE RAT RETINAS --- p.41 / Chapter 5.1.2.1. --- Enzyme-linked immunosorbent assay (ELISA) of mono- and oligonucleosomes --- p.42 / Chapter 5.1.2.2. --- In situ TUNEL --- p.42 / Chapter 5.1.3. --- BCL-2 AND RETINAL ISCHEMIA/REPERFUSION INJURY --- p.42 / Chapter 5.1.3.1. --- Immunohistochemistry of Bcl-2 --- p.42 / Chapter 5.1.3.2. --- Double labelling of Bcl-2 and TUNEL --- p.43 / Chapter 5.1.3.3. --- In situ RT-PCR for bcl-2 mRNA --- p.43 / Chapter 5.1.4. --- BAX AND RETINAL ISCHEMIA/REPERFUSION INJURY --- p.44 / Chapter 5.1.4.1. --- Immunohistochemistry of Bax --- p.44 / Chapter 5.1.4.2. --- Double labelling of Bax and TUNEL --- p.45 / Chapter 5.1.4.3. --- In situ RT-PCR for bax mRNA --- p.45 / Chapter 5.1.5. --- P53 IMMUNOREACTIVITY AT VARIOUS TIME AFTER REPERFUSION --- p.46 / Chapter 5.2. --- LOSS OF INNER RETINAL ELEMENTS IN THE RETINAL DYSTROPHIC ROYAL COLLEGE OF SURGEON (RCS) RATS --- p.47 / Chapter 5.2.1. --- HISTOPATHOLOGY --- p.47 / Chapter 5.2.2. --- MORPHOMETRY OF CELLS IN THE RGCL AND INL --- p.47 / Chapter 5.2.3. --- IMMUNOHISTOCHEMISTRY OF BCL-2 AND BAX --- p.47 / Chapter 5.2.3.1. --- Bcl-2 --- p.47 / Chapter 5.2.3.2. --- Bax --- p.48 / Chapter 6. --- DISCUSSION --- p.49 / Chapter 6.1. --- RETINA ISCHEMIA AND REPERFUSION INDUCED LOSS OF RETINAL ELEMENTS --- p.51 / Chapter 6.1.1 --- REPERFUSION TIME DEPENDENT TISSUE RESPONSES IN RAT RETINAS --- p.51 / Chapter 6.1.2 --- ISCHEMIA/REPERFUSION INDUCED APOPTOSIS IN RAT RETINAS --- p.52 / Chapter 6.1.3 --- BCL-2 AND RETINAL ISCHEMIA/REPERFUSION INSULT --- p.53 / Chapter 6.1.4 --- BAX AND RETINAL ISCHEMIA/REPERFUSION INSULT --- p.58 / Chapter 6.1.5 --- P53 AND RETINAL ISCHEMIA/REPERFUSION INJURY --- p.60 / Chapter 6.2. --- LOSS OF INNER RETINAL ELEMENTS IN THE RETINAL DYSTROPHIC ROYAL COLLEGE OF SURGEON (RCS) RAT --- p.61 / Chapter 6.2.1. --- HISTOPATHOLOGY AND MORPHOMETRY --- p.62 / Chapter 6.2.2. --- BCL-2 --- p.63 / Chapter 6.2.3. --- BAX --- p.64 / Chapter 7. --- CONCLUSION --- p.65 / APPENDIX A FIGURES --- p.66 / APPENDIX B REFERENCES --- p.100

For half a century, the central tenet of protein science has been grounded on the idea that the three-dimensional structure of a protein underlies its function. However, increasing evidence of natively unstructured but functional proteins is accumulating. Termed as intrinsically disordered proteins (IDPs), they populate a number of different conformations in isolation. Interestingly, as part of their function, some IDPs become fully or partly structured upon interaction with their binding partners. This process, known as coupled folding and binding raises the question what comes first - folding of the IDP or binding to its partner protein followed by folding. This thesis focuses on understanding the role of disorder in protein- protein interactions using biophysical characterization. Over-representation of IDPs in complex network and signalling pathways emphasizes the importance of disorder. Conformational flexibility in IDPs facilitates post-translational modifications, which provides a neat way to modulate the residual structure. This can alter affinity of IDPs to their partners and it is speculated that bound like structures of IDPs speed association. The impact of phosphorylation was explored in the KID/KIX system: phosphorylation modulates only the dissociation kinetics increasing the lifetime of the bound complex, which may be important in signalling processes. Further, phi-value analysis applied to investigate the mechanism of interaction reveals that non-native interactions play a key role in this reaction, before the IDP consolidates its final structure in the bound complex. Promiscuous interaction of IDPs with their partners often results in complexes with differing affinities. Members of BCL-2 family were explored, and the results indicate that IDPs bind to the same partner protein with marginal variation in the association rates, but significant differences in dissociation rates are observed. Thus, it seems that in such homologous but competing network of proteins, disorder facilitates complexes with differing affinities by modulating dissociation rate, again altering the lifetime of the bound complex. The work presented here demonstrates that disorder plays a role in altering complex lifetimes. Perhaps being disordered permits a level of plasticity to IDPs to adapt the rates at which they bind/unbind to many target proteins. This may be why disorder is conserved and abundant in proteins involved in intricate signalling networks.

Thesis (M.S. in Cancer Biology)--Vanderbilt University, May 2007. / Title from title screen. Includes bibliographical references.

Poxviruses are renowned for encoding proteins that modulate virtually every aspect of the host immune system. One effective barrier against virus infection is apoptosis, a form of programmed cell death. Apoptosis is controlled at the mitochondria by pro- and anti-apoptotic members of the highly conserved Bcl-2 family of proteins, and two members in particular, Bak and Bax, are absolutely critical to the induction of cell death. Although poxviruses encode an array of effective inhibitors of apoptosis, only members of the Avipoxvirus genus, of which fowlpox virus is the prototypical member, encode proteins with obvious, albeit limited, sequence identity to cellular Bcl-2 proteins. Fowlpox virus, the prototypical avipoxvirus, encodes FPV039, a protein that possesses two of the four highly conserved Bcl-2 homology (BH) domains that characterise the Bcl-2 family. Here we demonstrate that, like cellular Bcl-2 proteins, FPV039 localised to the mitochondria where it prevented apoptosis induced by a variety of cytotoxic stimuli, including virus infection itself. FPV039 inhibited apoptosis induced by Bak and Bax through an interaction with Bak and activated Bax. FPV039 also interacted with a discrete subset of BH3-only proteins, the upstream activators of Bak and Bax, to prevent Bax activation in the first place. Additionally, we have characterised the function and mechanism of action of a novel deerpox virus protein, DPV022. Intriguingly, DPV022 lacks obvious homology to cellular Bcl-2 proteins but shares limited regions of amino acid identity with two other poxviral inhibitors of apoptosis, vaccinia virus F1L and myxoma virus M11L, which are themselves unrelated. Here we demonstrate that DPV022 localised to the mitochondria where it interacted directly with Bak and Bax to inhibit apoptosis, even in the absence all cellular anti-apoptotic Bcl-2 proteins. We have also embarked on a preliminary analysis of the apical events that initially trigger apoptosis during infection with vaccinia virus, the prototypical poxvirus. Accordingly, we demonstrate that the BH3-only protein Noxa contributed to the vaccinia virus-induced apoptotic response, possibly through an involvement with dsRNA. Together, this study represents a comprehensive analysis of the ways in which poxviruses manipulate the cellular Bcl-2 family of proteins, the arbiters of cell death. / Virology

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.