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• W2738239084 abstract "Donald E. Ayer, Leo Kretzner, and Robert N. Eisenman Division of Basic Sciences Fred Hutchinson Cancer Research Center Seattle, Washington 98104 Summary Myc family proteins appear to function through hetero- dimerization with the stable, conatitutively expressed bHLH-Zip protein, Max. To determine whether Max mediates the function of regulatory proteins other than Myc, we screened a kgtl 1 expression library with ra- diolabeted Max protein. One cDNA identified encodes a new member of the bHLH-Zip protein family, Mad. Human Mad protein homodimerizea poorly but binds Max in vitro, forming a sequence-specific DNA binding complex wfth properties very similar to those of Myc- Max. Both Myc-Max and Mad-Max heterocomplexea are favored over Max homodlmenr, and, unlike Max homodimers, the DNA binding activity of the hetero- dimers is unaffected by CKll phosphorylation. Mad does not associate with Myc or with representative bHLH, bZlp, or bHLH-Zip proteins. in vivo transactiva- tion assays suggest that Myc-Max and Mad-Max com- plexes have opposing functions in transcription and that Max plays a central role in this network of tran- scription factors. Introduction Heterotypic protein interactions have emerged as a major regulatory mechanism governing the function of transcrip- tion factors. Studies on several different classes of tran- scription factors have demonstrated that both the nature and the relative abundance of individual subunits can act as positive or negative modulators of transcription factor activity (for review see Jones, 1990). The activities of the bHLH, bZip, and bHLH-Zip transcription factors are regulated by homodimerization and/or heterodimerization (Jones, 1990; Kadesch, 1992). The proteins in this class are structurally similar in that they all possess a basic region (b), required for specific DNA binding, linked to two motifs, either singly or in combination, that mediate protein-protein interaction. The HLH region can be mod- eled as two amphipathic helices separated by a flexible “loop” (Murre et al., 1989a, 1989b), while the Zip domain has been shown to form a coiled-coil structure (O’Shea et al., 1989). The c-, N-, and L-Myc proteins belong to the bHLH-Zip class suggesting that their activity may be regu- lated by homotypic or heterotypic interaction (Landschulz et al., 1988; Kouzarides and Ziff, 1988; Lijscher and Eisen- man, 1990). Myc proteins homodimerize and bind DNA poorly, if at all, at physiological levels (Dang et al., 1991) and have not been found to interact with other proteins of the bHLH, bZip, or bHLH-Zip groups, with the exception of Max (Blackwood and Eisenman, 1991; Prendergast et al., 1991). Max is a bHLH-Zip protein initially identified by screening a B cell cDNA expression library with the bHLH- Zip region of c-Myc(Blackwood and Eisenman, 1991). Max homodimers and the Myc-Max heterodimer bind the se- quence CACGTG; however, the binding of the heterodim- eric complex is stronger relative to that of Max homodi- mers, suggesting that heterodimers are the preferred species (Blackwell et al., 1990; Prendergast and Ziff, 1991; Blackwood and Eisenman, 1991; Berberich et al., 1992). The major Max translation products have been identified in different cell types as 21 kd (Max) and 22 kd (Max9) proteins that differ by a 9 amino acid insertion N-terminal to the basic region (Blackwood et al., 1992a). Both forms of Max have been shown to associate with Myc in vivo and in vitro and Myc-Max heterodimers with CACGTG binding activity can be coimmunoprecipitated from cells (Black- wood et al., 1992a). The DNA binding activity of the Myc- Max immunoprecipitates is significantly increased by phosphatase treatment (E. M. Blackwood, unpublished data), consistent with recent evidence showing that casein kinase II (CKII), which phosphorylates Max in vitro and vivo, inhibits the DNA binding activity of Max homodimers but not Myc-Max heterodimers (Blackwood et al., 1992a; Berberich and Cole, 1992; B. Ltischer, E. M. Blackwood, L. K., and D. E. A., unpublished data). In contrast with Myc, which is highly regulated and whose synthesis is rapidly modulated during cell cycle entry and exit (Liischer and Eisenman, 1990, for recent review), Max is present in nonproliferating GO cells, and its abundance does not change during the GO/G1 transition (Blackwood et al., 1992a, 1992b; Berberich 1992). Moreover, Max was found to be a very stable protein (with a half-fife greater than 18 hr), while Myc is known to be extraordinarily unstable (with a half-life of less than 45 min) (Hann et al., 1985; Rabbitts 1985) pulse-chase experiments showed My&s half-life to be unaffected by dimerization with Max (Blackwood et al., 1992a). Further- more, Max appears to be present in significant excess over Myc (E. M. Blackwood, unpublished data). Therefore, heterocomplex formation in vivo is likely to be dependent on the rate of synthesis Myc. Recent experiments show that the relative amounts of Max homodimers and Myc-Max heterodimers can affect the transcriptional activity of a reporter gene containing promoter-proximal Myc-Max-binding sites (Kretzner et al., 1992). Transcription from such a reporter gene is stimu- lated by Myc overexpression and repressed by Max over- expression. Activation is dependent on N- and C-terminal regions of Myc, while repression is dependent on the Max DNA-binding domain. Max-induced repression is allevi- ated by overexpression of Myc, suggesting that the shift from Max homodimers to Myc-Max heterodimers can lead from repression to activation. These properties of Myc and Max are consistent with experiments demonstrating the presence of an N-terminal activation domain in Myc (Kato" @default.
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• W2738239084 date "1993-01-01" @default.
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• W2738239084 title "IMad: A Heterodimeric Partner for Max That Antagunizes Myc Transcri ACtiVii" @default.
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