Myc family oncoproteins function through a common pathway to transform normal cells in culture: cross-interference by Max and trans-acting dominant mutants.

Abstract

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 coimmunoprecipitation 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 cotransfections. 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.

Mechanisms of apoptosis by c-Myc

“…Phosphorylation and alternate splicing proximal to the basic region inhibit the ability of Max homodimers to associate with DNA in cells (Berberich and Cole, 1992;Prochownik and Van Antwerp, 1993;Zhang et al, 1997). Max association and DNA binding are required for transcriptional activation of target genes by c-Myc as well as its ability to drive proliferation, malignant cell transformation, and apoptosis (Amati et al, 1992;Kretzner et al, 1992a,b;MaÈ kelaÈ et al, 1992;Mukherjee et al, 1992;Prendergast et al, 1992;Amati et al, 1993a,b;Gu et al, 1993). Access to CACGTG binding sites in target genes may be regulated by CpG methylation of the central dinucleotide .…”

Sequential expression of the MAD family of transcriptional repressors during differentiation and development

“…At the center of this network is MAX, a widely expressed and stable bHLH-Zip protein Eisenman, 1991, Prendergast et al, 1991). MAX is an obligatory heterodimeric partner for the MYC proteins in mediating their functions as sequence-speci®c DNAbinding transcriptional activators, that regulate cell cycle progression, transformation and apoptosis (Kretzner et al, 1992;Amin et al, 1993;Mukherjee et al, 1992;Amati et al, 1993a,b). MAX can also form heterodimers with at least two other types of bHLHZip proteins, the MAD proteins (MAD1, MXI1, MAD3 and MAD4) Zervos et al, 1993;Hurlin et al, 1995a) and the recently identi®ed MNT protein (Hurlin et al, 1997a;Meroni et al, 1997).…”

Max and inhibitory c-Myc mutants induce erythroid differentiation and resistance to apoptosis in human myeloid leukemia cells

“…Myc/Max activates transcription of reporter genes carrying Ems in their promoters, while the homodimer Max/Max is inactive as a transcriptional activator Amin et al, 1993;Gu et al, 1993). Also, the overexpression of Max results in suppression of cell transformation mediated by c-Myc (Makela et al, 1992;Prendergast et al, 1991;Mukherjee et al, 1992;Amati et al, 1993a;Gu et al, 1993;Koskinen et al, 1994;Lindeman et al, 1995). These data are consistent with the idea that inactive Max/Max dimers compete in vivo with Myc/Max for common DNA binding sites.…”