Nuclear tumor necrosis factor receptor-associated factor 6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through small ubiquitin-related modifier-1 modification.
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an adaptor/scaffold protein that mediates several important signaling pathways, including the tumor necrosis factor-R:NF-kappaB pathway, involved in immune surveillance, inflammation, etc. Because most studies of TRAF6 function have focused primarily on its role as an adaptor molecule in signaling pathways in the cytoplasm, the potential functions of TRAF6 in other cellular compartments has not been previously investigated. Here, we demonstrate that TRAF6 resides not only in the cellular cytoplasm but is also found in the nuclei of both normal and malignant B lymphocytes. TRAF6 does not possess a nuclear localization signal but enters the nucleus through the nuclear pore complex containing RanGap1. Chromatin immunoprecipitation cloning experiments demonstrated that nuclear TRAF6 associates with c-Myb within the 5'-end of the c-Myb promoter. Further analysis showed that nuclear TRAF6 is modified by small ubiquitin-related modifier-1, interacts with histone deacetylase 1, and represses c-Myb-mediated transactivation. Thus, TRAF6 negatively regulates c-Myb through a novel repressor function in the nuclei of both normal and malignant B-lymphocytes that could represent a novel control mechanism that maintains cell homeostasis and immune surveillance.
Pham
Lan V
LV
Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Zhou
Hai-Jun
HJ
Lin-Lee
Yen-Chiu
YC
Tamayo
Archito T
AT
Yoshimura
Linda C
LC
Fu
Lingchen
L
Darnay
Bryant G
BG
Ford
Richard J
RJ
D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020690:GTPase-Activating Proteins; D006801:Humans; D007157:Immunologic Surveillance / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D022022:Nuclear Pore / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured
D020690:GTPase-Activating Proteins; D016328:NF-kappa B; D020598:Proto-Oncogene Proteins c-myb; C092317:RANGAP1 protein, human; D018124:Receptors, Tumor Necrosis Factor; D025841:Small Ubiquitin-Related Modifier Proteins; D048029:TNF Receptor-Associated Factor 6