Phosphorylation sites mapping in the N-terminal domain of c-myc modulate its transforming potential.
The nuclear proto-oncoprotein c-Myc is involved in the regulation of cell growth and differentiation. c-Myc is phosphorylated at multiple sites in vivo, two of which we have identified near the amino terminus. In chicken Thr-61/Ser-65 are phosphorylated, as are the comparable positions, Thr-58/Ser-62 in human c-Myc. These residues are located within a domain that is implicated in transactivation and is important for the transforming potential of the protein. Furthermore, these phosphorylation sites or nearby amino acids are frequently mutated in v-myc and in several c-myc genes from Burkitt's lymphoma cells. In vitro these two phosphorylation sites can be modified by glycogen synthase kinase 3 and mitogen activated protein kinase. To address their biological importance we mutated these amino terminal phosphorylation sites separately and together. Stably transfected Rat1A cells expressing the mutated proteins have an increased growth potential in soft agar compared to wt-c-myc transfectants. These altered transformation characteristics indicate that Myc function may be negatively regulated by the amino terminal phosphorylation.
Henriksson
M
M
Institute for Molecular Biology, Hannover Medical School, Germany.
Bakardjiev
A
A
Klein
G
G
Lüscher
B
B
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D002645:Chickens; D004273:DNA, Neoplasm / Q000235:genetics; D038341:Glycogen Synthase Kinases; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000378:metabolism* / Q000502:physiology*; D051381:Rats; D015183:Restriction Mapping; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000596:Amino Acids; D004273:DNA, Neoplasm; D008934:Mitogens; D016271:Proto-Oncogene Proteins c-myc; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases