The C-Myc Oncogenic Transcription Factor

Gardner, Lee & Dang

The c-Myc Oncogenic Transcription Factor
L. Gardner, L. Lee, and C. Dang
(Adapted from myc oncogene, Encyclopedia of Cancer)

Introduction
In 1911 Peyton Rous observed that chicken sarcoma could be transmitted through cellfree extracts from the tumors, suggesting that a virus could be the etiologic agent of these
sarcomas. On the basis of the work by Bishop andcoworkers, studies of a specific subgroup of
avian retrovirus, which induces myeloid leukemia, sarcomas, liver, kidney, and other tumors in
chickens, led to the identification of the v-myc oncogene. The discovery of a homologous gene,
termed c-myc, in chicken supported the view that oncogenic avian retroviruses could capture
cellular growth regulatory genes and transmit the activated gene. Thefinding that human
cancers frequently display altered expression of human c-myc underscore the importance of this
gene in the cause of human cancers.
Significant progress has been made over the last two decades in our understanding of the
function of c-myc in normal cells and in cancer cells. In contrast to the tightly regulated c-myc
gene in normal cells, which only express the gene when cellsactively divide, cancer cells may
express the gene in an uncontrolled fashion as the result of genetic aberrations. It is now wellestablished that the deregulated expression of c-myc plays a significant role in human cancer
development. The c-Myc protein or the c-myc gene is overexpressed in a wide variety of human
cancers with 80% of breast cancers, 70% of colon cancer, 90% of gynecologicalcancers, 50%
of hepatocellular carcinomas and a variety of hematological tumors possessing abnormal myc

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expression. On the basis of these frequencies, it is estimated that approximately 100,000 US
cancer deaths per year are associated with changes in the c-myc gene or its expression. The
clinical significance of myc gene alterations in human cancers is best illustratedby
prognostication by N-myc amplification in neuroblastoma, and the sine qua non chromosomal
translocation affecting c-myc in Burkitt’s lymphoma.
Over the past decade, the Myc proteins emerged as a transcription factors, able to
regulate gene expression. In this brief review, the structure of c-Myc, the other cellular
homologs N-Myc and L-Myc, Myc transactivation, and some of the c-Myctarget genes will be
highlighted. The function of Myc in normal cellular function, particularly in proliferation and
differentiation, will be examined. Specific mechanisms for Myc overexpression in cancer, and
the effect of this overexpression on the cell cycle, apoptosis, differentiation, cellular metabolism
and genomic instability will be discussed.

Myc Structure and Function
The c-myc geneis located on human chromosome 8q24, consisting of three exons. Its
transcription may be initiated at one of three promoters. Translation at the AUG start site in the
second exon produces a major 439 amino acid, 64 kDa c-Myc protein. Alternative translational
initiation start sites result in both longer and shorter forms of the protein, termed p67 Myc and
MycS, respectively. The c-Myc proteinis O-linked glycosylated and phosphorylated, and these
modifications may alter the protein half-life. The c-Myc sequence contains several conserved Nterminal domains, termed Myc boxes, which are found in closely related proteins, N-Myc and LMyc (Figure 1).

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NTS

NTS
PO4
O-GlcNAc

Max

Max
Myc

T RD
MBI

b HLH LZ

b HLH LZ

Mad
SID

MBII
NTSCACGTG

target gene

Figure 1. The diagram depicts the heterodimerization of Max with either c-Myc or Mad proteins. The
heterodimeric transcription factors regulate transcription of a hypothetical target gene through the E-box element, 5'CACGTG-3'. c-Myc-Max activates transcription possibly through histone acetylation and direct interaction with the
transcriptional machinery. Mad-Max...