c-myc box II mutations in Burkitt's lymphoma-derived alleles reduce cell-transformation activity and lower response to broad apoptotic stimuli.
In addition to c-myc rearrangement, over 50% of Burkitt's lymphoma cases present clustered mutations in exon 2, where many of the functional activities of c-Myc protein are based. This report describes the functional consequences induced by tumour-derived c-myc mutations located in c-myc box II. Two mutated alleles were studied, focusing on the P138C mutation, and compared to wild-type c-myc. The c-Myc transformation, transactivation and apoptosis activities were explored based on cells over-expressing c-Myc. While the transcriptional activation activity was not affected, our experiments exploring the anchorage-independent growth capacity of c-Myc-transfected Rat1a cells showed that c-Myc box II mutants were less potent than wild-type c-Myc in promoting cell transformation. Considering the possibility that these mutations could be interfering with the ability of c-Myc to promote apoptosis, we tested c-Myc-transfected Rat1a fibroblasts under several conditions: serum deprivation-, staurosporine- and TNFalpha-induced cell death. Interestingly, the mutated alleles were characterized by an overall decrease in ability to mediate apoptosis. Our study indicates that point mutations located in c-Myc box II can decrease the ability of the protein to promote both transformation and apoptosis without modifying its transactivating activity.
Kuttler
F
F
Department of Haematology and Cell Biology, Institut d'Etude et de Transfert de Genes, University Hospital Jean Minjoz, 25030 Cedex Besançon, France.
Amé
P
P
Clark
H
H
Haughey
C
C
Mougin
C
C
Cahn
J Y
JY
Dang
C V
CV
Raffeld
M
M
Fest
T
T
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D017124:Conserved Sequence; D010641:Phenotype; D017354:Point Mutation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000502:physiology*; D051381:Rats; D011960:Receptors, Estrogen / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D013629:Tamoxifen; C016601:afimoxifene; D019311:Staurosporine