Regulation of NF-κB by PML and PML-RARα.
Promyelocytic Leukemia (PML) is a nuclear protein that forms sub-nuclear structures termed nuclear bodies associated with transcriptionally active genomic regions. PML is a tumour suppressor and regulator of cell differentiation. We demonstrate that PML promotes TNFα-induced transcriptional responses by promoting NF-κB activity. TNFα-treated PML-/-cells show normal IκBα degradation and NF-κB nuclear translocation but significantly reduced NF-κB DNA binding and phosphorylation of NF-κB p65. We also demonstrate that the PML retinoic acid receptor-α (PML-RARα) oncofusion protein, which causes acute promyelocytic leukemia, inhibits TNFα induced gene expression and phosphorylation of NF-κB. This study establishes PML as an important regulator of NF-κB and demonstrates that PML-RARα dysregulates NF-κB.
Department of Biochemistry, University College Cork, Cork, Ireland.
Abrar
A
Ahmed
Shenzhen Institutes of Advanced Technology, Shenzhen, China.
Xiaochun
X
Wan
GLAZgo Discovery Centre, Institute of Infection, Immunity &Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Izaskun
I
Mitxitorena
Department of Biochemistry, University College Cork, Cork, Ireland.
Andrew J
AJ
Lindsay
Department of Pathology, Beth Israel Deaconess Medical Centre, Harvard University, Boston, MA, 02215, USA.
Pier
P
Paolo Pandolfi
Department of Biochemistry, University College Cork, Cork, Ireland.
Mary W
MW
McCaffrey
Paul O'Gorman Leukaemia Research Centre, College of Medicine, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, United Kingdom.
Karen
K
Keeshan
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Youhai H
YH
Chen
Centre for Immunobiology, Institute of Infection, Immunity &Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Ruaidhrí J
RJ
Carmody
D000818:Animals; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D063990:Gene Ontology; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D058977:Molecular Sequence Annotation; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D000072000:NF-KappaB Inhibitor alpha; C070576:PML protein, human; D008156:Luciferases