Functional analysis of Burkitt's lymphoma mutant c-Myc proteins.
The c-myc gene encodes a sequence-specific DNA binding protein that activates transcription of cellular genes. Transcription activation by Myc proteins is regulated by phosphorylation of serine and threonine residues within the transactivation domain and by complex formation with the retinoblastoma-related protein p107. In Burkitt's lymphoma, missense mutations within the c-Myc transactivation domain have been found with high frequency. It has been reported that mutant c-Myc proteins derived from Burkitt's lymphoma cell lines are resistant to inhibition by p107, thus providing a rationale for the increased oncogenic activity of these mutant c-Myc proteins. It has been suggested that these mutant c-Myc proteins resist down-modulation by p107 because they lack cyclin A-cdk2-dependent phosphorylation. Here, we have examined three different Burkitt's lymphoma mutant c-Myc proteins found in primary Burkitt's lymphomas and one mutant c-Myc protein detected in a Burkitt's lymphoma cell line. All four have an unaltered ability to activate transcription and are sensitive to inhibition of transactivation by p107. Furthermore, we provide evidence that down-modulation of c-Myc transactivation by p107 does not require phosphorylation of the c-Myc transactivation domain by cyclin A-cdk2. Our data indicate that escape from p107-induced suppression is not a general consequence of all Burkitt's lymphoma-associated c-Myc mutations, suggesting that other mechanisms exist to deregulate c-Myc function.
Smith-Sørensen
B
B
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
Hijmans
E M
EM
Beijersbergen
R L
RL
Bernards
R
R
D000595:Amino Acid Sequence; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D016259:Genes, myc; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides; D012516:Osteosarcoma; D010957:Plasmids; D017354:Point Mutation; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012694:Serine; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D009838:Oligodeoxyribonucleotides; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D012694:Serine