Myc family oncoproteins function through a common pathway to transform normal cells in culture: cross-interference by Max and trans-acting dominant mutants.
The myc family of cellular oncogenes encodes three highly related nuclear phosphoproteins (c-Myc, N-Myc, and L-Myc) that are believed to function as sequence-specific transcription factors capable of regulating genes important in cellular growth and differentiation. Current evidence indicates that Myc family proteins exist as biologically active heterodimeric complexes in association with another helix-loop-helix leucine zipper phosphoprotein, Max. We have investigated the common and unique properties among the Myc family, as well as the physiological role of Max in the regulation of Myc family function. We demonstrate that trans-activation-incompetent mutants of one Myc family member can act in trans to dominantly suppress the cotransformation activities of all three Myc oncoproteins, indicating that the Myc family functions through common genetic elements in its cellular transformation pathways. Employing co-immunoprecipitation with either anti-Myc or anti-Max antibodies, we show that the transfected normal c-Myc, N-Myc, and L-Myc oncoproteins associate with the endogenous Max protein in REF transformants, indicating that the Max interaction represents at least one component common to Myc family function. In addition, we observed a striking reduction in Myc cotransformation activity when a Max expression construct was added to myc/ras co-transfections. We discuss these biological findings in the context of a proposed model for Myc/Max function and regulation in which Max serves as either an obligate partner in the Myc/Max transcriptional complex or as a repressor in the form of a transcriptionally inert Max/Max homodimer capable of occupying Myc/Max-responsive gene targets.
Mukherjee
B
B
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.
Morgenbesser
S D
SD
DePinho
R A
RA
D050976:Basic-Leucine Zipper Transcription Factors; D015152:Blotting, Northern; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016259:Genes, myc / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D011233:Precipitin Tests; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C067850:Myc associated factor X; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors