title: HOXA1 binds RBCK1/HOIL-1 and TRAF2 and modulates the TNF/NF-κB pathway in a transcription-independent manner.
abstract: HOX proteins define a family of key transcription factors regulating animal embryogenesis. HOX genes have also been linked to oncogenesis and HOXA1 has been described to be active in several cancers, including breast cancer. Through a proteome-wide interaction screening, we previously identified the TNFR-associated proteins RBCK1/HOIL-1 and TRAF2 as HOXA1 interactors suggesting that HOXA1 is functionally linked to the TNF/NF-κB signaling pathway. Here, we reveal a strong positive correlation between expression of HOXA1 and of members of the TNF/NF-κB pathway in breast tumor datasets. Functionally, we demonstrate that HOXA1 can activate NF-κB and operates upstream of the NF-κB inhibitor IκB. Consistently, we next demonstrate that the HOXA1-mediated activation of NF-κB is non-transcriptional and that RBCK1 and TRAF2 influences on NF-κB are epistatic to HOXA1. We also identify an 11 Histidine repeat and the homeodomain of HOXA1 to be required both for RBCK1 and TRAF2 interaction and NF-κB stimulation. Finally, we highlight that activation of NF-κB is crucial for HOXA1 oncogenic activity.
authors.affiliation: Animal Molecular and Cellular Biology Group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve 1348, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Taminiau
authors.affiliation: Animal Molecular and Cellular Biology Group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve 1348, Belgium.
authors.forename: Amandine
authors.initials: A
authors.lastname: Draime
authors.affiliation: Animal Molecular and Cellular Biology Group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve 1348, Belgium.
authors.forename: Janne
authors.initials: J
authors.lastname: Tys
authors.affiliation: Animal Molecular and Cellular Biology Group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve 1348, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lambert
authors.affiliation: Animal Molecular and Cellular Biology Group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve 1348, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Vandeputte
authors.affiliation: Animal Molecular and Cellular Biology Group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve 1348, Belgium.
authors.forename: Nathan
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Cellular Biology Research Unit, Université de Namur, Namur 5000, Belgium.
authors.forename: Patricia
authors.initials: P
authors.lastname: Renard
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Rotterdam 3015, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.affiliation: Animal Molecular and Cellular Biology Group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve 1348, Belgium rene.rezsohazy@uclouvain.be.
authors.forename: René
authors.initials: R
authors.lastname: Rezsöhazy
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D066264:Datasets as Topic; D004843:Epistasis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006639:Histidine / Q000378:metabolism; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D000072417:Protein Domains; D017384:Sequence Deletion; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099261:Homeobox A1 Protein
chemical_list: D006639:Histidine; D018398:Homeodomain Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D047992:TNF Receptor-Associated Factor 2; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; D000099261:Homeobox A1 Protein; C504507:RBCK1 protein, human