Myc meets its max

Abstract

c-myc, the earliest discovered and perhaps most prominent nuclear oncogene, has been implicated in the control of normal cell proliferation and the transformation and differentiation of many cell lineages (reviewed in Cole, 1936; Luscher and Eisenman, 1999). c-Myc represents the paradigm for two broad classes of transcription factors that contain either the basic/helix-loop-helix (HLH; Murre et al., 1939a) or the basic/leucine repeat structure (LR; Landschulz et al., 19BB). Thus, it is’particularly ironic that the direct demonstration of a function for the c-Myc protein has only recently been achieved with two reports of the cloning of a heterodimeric partner of c-Myc, called Max, that facilitates sequence-specific DNA-binding activity. A partner was predicted because c-Myc, like c-Fos, contains a leucine repeat with many charged residues at the coiledcoil interface that seem to prevent homodimer formation (O’Shea et al., 1989). If Max is the one and true partner of c-Myc, it opens new avenues of investigation that will finally address the key issue of how c-Myc can exert such a diverse range of biological activities. Myc Functions in DNA Binding as a Heterodlmer The clear demonstration of a DNA-binding function for Myc came first from the elegant use of a potentially powerful approach to the study of protein dimers, that of direct screening of a bacterial expression library with labeled protein. Blackwood and Eisenman (1991) used a labeled fusion protein containing the C-terminus of c-Myc to isolate a clone encoding a novel protein, Max. Like Myc itself, Max contains adjacent basic, HLH, and LR domains. Max forms heterodimers with all three Myc proteins (c-, N-, and L-Myc) but does not dimerize wlth other HLH proteins, even those that also contain combined HLHlLR domains such as TFE?t (Beckmann et al., 1999) USF (Gregor et al., 1990) and AP-4 (Hu et al., 1990). The Myc-Max heterodimer binds to the sequence CACGTG, which has been shown to bind weakly to Myc homodimers that form at very high protein concentrations (Blackwell et al., 1990). An alternative PCR approach that led to the cloning of max employed primers chosen to match conserved domains of Myc (Prendergast et al., 1991). One of the amplified cDNA molecules matched the sequence of max reported by Blackwood and Eisenman (1991). Analogous experiments demonstrated heterodimer formation and sequence-specific DNA binding. However, major differences were reported in the two studies in the migration of the Myc-Max complex, and in homodimer binding activity; these discrepancies are unresolved but seem difficult to attribute to reagents or constructs. The structure of Max appears to be extremely simple; it is comprised of only 169 amino acids, 99 of which constitute the DNA-bindingldimerization domain (see figure). Minireview