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) (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.
Starczynowski
D T
DT
Department of Biology, Boston University, Boston, MA 02215, USA.
Trautmann
H
H
Pott
C
C
Harder
L
L
Arnold
N
N
Africa
J A
JA
Leeman
J R
JR
Siebert
R
R
Gilmore
T D
TD
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002472:Cell Transformation, Viral; D002645:Chickens; D024202:Electrophoretic Mobility Shift Assay; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D017404:In Situ Hybridization, Fluorescence; D007668:Kidney / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism; D008479:Mediastinal Neoplasms / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D000090063:Proto-Oncogene Mas; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013154:Spleen / Q000378:metabolism / Q000821:virology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C000715470:MAS1 protein, human; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; D020569:Proto-Oncogene Proteins c-rel; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D051550:I-kappa B Kinase