Solomon, David Louis Charles; (1997) The mechanisms of c-Myc function. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The c-Myc protein (Myc) is involved in the control of cell proliferation, differentiation and programmed cell death. It has considerable structural similarity to transcription factors, including a helix-loop-helix and a leucine zipper (both known dimerisation motifs), a basic region able to bind sequence-specifically to DNA and a region in the N-terminus that can activate transcription when fused to a heterologous DNA-binding domain. A related protein (Max) was identified as a dimerisation partner for Myc; both Myc/Max and Max/Max can bind to DNA of sequence CACGTG. I show herein that Myc can activate transcription in mammalian cells in a sequence-specific manner and show that the basic region, N- terminal regions and dimerisation domains are essential for transactivation, as is dimerisation with Max. I have investigated the DNA-binding properties of Myc and Max and have determined the preferred binding sites for the Myc/Max and Max/Max dimers. Although both bind to CACGTG, the Myc/Max complex is more discriminatory than the Max homodimer at positions flanking this core sequence. In particular a 5' flanking T residue (or a 3'A) is disfavoured. A model for gene regulation by the Myc family of proteins is discussed. In an effort to understand the means by which Myc acts, I have also investigated possible target genes for Myc that mediate proliferation and show that cyclin E, but not cyclin Dl, is induced by Myc independently of new protein synthesis. Moreover, Myc induces cyclin E associated kinase activity. This regulation occurs at two levels: increased transcription of the cyclin E gene and activation of the kinase activity of cyclin E complexes, at least partly due to loss of the inhibitor p27Kip1. Induction of cyclin E protein alone is sufficient to induce apoptosis but not proliferation. The role of cyclin E in Myc function is discussed.

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