The role of c-myc during normal B cell proliferation, and as B cells undergo malignant transformation.

Abstract

c-myc is a protooncogene that encodes a 64 kDa nuclear protein containing carboxy-terminal leucine zipper and helix-loop-helix domains [1]. These two structural features predict a role for the Myc oncoprotein as a transcription factor requiring a protein partner. Blackwell and colleagues [2] demonstrated that Myc binds DNA in a sequence specific fashion by recognizing the sequence CAC(G/A)TG. This same group also isolated Max, a leucine zipper and helix-loop-helix protein partner for Myc [3]. Although Myc and Max homodimers can bind CAC(G/A)TG motifs with weak affinity [2, 3], the Myc:Max heterodimers demonstrate a much higher binding affinity, indicating that relative cellular levels of both these phosphoproteins is important. Max, but not Myc, is present in quiescent cells, and functions as a transcription repressor [4, 5]. Therefore, the induction of Myc expression as cells enter the cell cycle not only countermands the repression of gene expression elicited by the Max homodimers, but also results in the gradual increase in Myc:Max heterodimers that initiate growth-related gene expression. Two growth related genes known to be regulated by Myc are ornithine decarboxylase [6] and cdc25A phosphatase [7]. The appearance of Myc:Max heterodimers not only occur as cells progess into the G1 stage of the cell cycle, but are required for cells to progress through the G1 cell cycle stage [8]. Thus, unlike other oncoproteins that appear early during cell cycle progression, such as Fos, both c-myc mRNA and Myc protein are expressed at multiple cell cycle stages [9–11]. This indicates that the protein products of Myc regulated genes are available during the entire mammalian cell cycle.