Mutation of an IKK phosphorylation site within the transactivation domain of REL in two patients with b-cell lymphoma enhances REL's in vitro transforming activity

The human c-rel proto-oncogene (REL) encodes a subunit of the nuclear factor-kappaB (NF-kappaB) transcription factor. In this report, we have identified an identical point mutation in two human B-cell lymphomas (follicular (FL) and mediastinal) that changes serine (Ser)525 (TCA) to proline (Pro) (CC...

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Published in:	Oncogene Vol. 26; no. 19; pp. 2685 - 2694
Main Authors:	STARCZYNOWSKI, D. T, TRAUTMANN, H, POTT, C, HARDER, L, ARNOLD, N, AFRICA, J. A, LEEMAN, J. R, SIEBERT, R, GILMORE, T. D
Format:	Journal Article
Language:	English
Published:	Basingstoke Nature Publishing 26-04-2007 Nature Publishing Group
Subjects:	Amino Acid Sequence Animals B-cell lymphoma Biological and medical sciences Blotting, Western Cancer Causes of Cell death Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cell Transformation, Viral Chickens DNA binding proteins Electrophoretic Mobility Shift Assay Fluorescent Antibody Technique, Indirect Fundamental and applied biological sciences. Psychology Gene expression Gene mutations Genetic aspects Genetics Health aspects Hematologic and hematopoietic diseases Humans I-kappa B Kinase - physiology In Situ Hybridization, Fluorescence Kidney - metabolism Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Luciferases - metabolism Lymphocytes B Lymphoma Lymphoma, B-Cell - genetics Lymphoma, B-Cell - metabolism Lymphoma, Follicular - genetics Lymphoma, Follicular - metabolism Manganese Mediastinal Neoplasms - genetics Mediastinal Neoplasms - metabolism Medical sciences Molecular and cellular biology Molecular Sequence Data Mutation NF-kappa B - genetics NF-kappa B - metabolism NF-κB protein Non-Hodgkin's lymphomas Phosphorylation Point mutation Point Mutation - genetics Proline Promoter Regions, Genetic - genetics Proto-Oncogene Proteins c-rel - genetics Proto-Oncogene Proteins c-rel - metabolism Rel protein Sequence Homology, Amino Acid Spleen Spleen - metabolism Spleen - virology Superoxide dismutase Transcriptional Activation Transformed cells Tumor Necrosis Factor-alpha - pharmacology Tumor necrosis factor-TNF Tumor necrosis factor-α Tumor suppressor genes Canada Germany Human human mutation Phosphorylation NF-KB c-Rel Malignant hemopathy Carcinogenesis In vitro Lymphoma Lymphoproliferative syndrome Malignant transformation Rel Mutation Protooncogene
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Summary:	The human c-rel proto-oncogene (REL) encodes a subunit of the nuclear factor-kappaB (NF-kappaB) transcription factor. In this report, we have identified an identical point mutation in two human B-cell lymphomas (follicular (FL) and mediastinal) that changes serine (Ser)525 (TCA) to proline (Pro) (CCA) within the REL transactivation domain. This mutation was not identified in a similarly sized cohort of healthy individuals. In the mediastinal B-cell lymphoma, the mutation in REL is of germ-line origin. In both tumors, the S525P mutant allele is over-represented. REL-S525P shows enhanced in vitro transforming activity in chicken spleen cells. REL-S525P has a reduced ability to activate the human manganese superoxide dismutase (MnSOD) promoter in A293 cells; however, the MnSOD protein shows increased expression in REL-S525P-transformed chicken spleen cells as compared to wild-type REL-transformed cells. Ser525 is a site for phosphorylation by IkappaB kinase (IKK) in vitro. The S525P mutation reduces IKKalpha- and tumor necrosis factor (TNF)alpha-stimulated transactivation by a GAL4-REL protein. Furthermore, REL-S525P-transformed chicken spleen cells are more resistant to TNFalpha-induced cell death than cells transformed by wild-type REL. These results suggest that the S525P mutation contributes to the development of human B-cell lymphomas by affecting an IKKalpha-regulated transactivation activity of REL.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/sj.onc.1210089