Regular articleMechanisms of c-myc-mediated transcriptional repression of growth arrest genes
Introduction
The nuclear phosphoprotein c-Myc is a central regulator of cellular proliferation and cell growth. Deregulated expression of Myc family proteins (c-, N-, and L-Myc) has been demonstrated in many types of cancer (for reviews, see [1], [2], [3], [4]). In the past 10 years c-Myc has been under detailed investigation in an effort to understand the role of this molecule in tumor progression. c-Myc is a multifaceted protein that controls regulation of the cell cycle and cell growth, activates genomic instability, and stimulates angiogenesis, cell transformation, and apoptosis (for a recent review, see [5]).
The proto-oncogene c-myc executes its multiple activities mostly through the transcriptional regulation of target genes. The role of c-Myc in the activation of transcription is well described. c-Myc is a basic helix–loop–helix–leucine zipper (bHLH-LZ) transcription factor (Fig. 1) that binds to a CACGTG sequence (E-box) as part of a heterodimeric complex with another bHLH-LZ protein, Max, and activates transcription of promoters that carry such an element [6]. Max might also form heterodimers with other bHLH-LZ proteins, including Mad1, Mxi1, Mad3, Mad4, and Mnt (for a review, see [7]). These alternative heterodimers can compete for DNA binding with the Myc–Max complex and repress transcription through deacetylation of histones, thus antagonizing the transcriptional and transforming activities of c-Myc.
The c-Myc protein consists of three domains: N-terminal, central, and C-terminal (Fig. 1). The N-terminal domain of c-Myc is involved in activation of transcription and it includes the highly conserved Myc Box regions (MB1 and MB2) that are unique for the members of the Myc family (Fig. 1). The C-terminal part of Myc contains the bHLH-LZ motif that is necessary for interaction with Max and other proteins (Fig. 1). Myc promotes cell cycle progression by coordinated regulation of expression of a number of genes. c-Myc activates expression of cell cycle promoting genes such as cdc25A, cdk4, and cyclins D2, -E, and -A and suppresses expression of cell cycle/growth arrest genes (gas1, p15, p21, p27, and gadds) (for reviews, see [5], [8]).
Interestingly, there are indications that for cell transformation activation of transcription by Myc is less important than the repression of Myc target genes. For example, a naturally occurring truncated form of Myc, MycS (Fig. 1), lacks a functional transactivation domain, but retains the ability to repress promoters of the growth arrest genes, stimulate proliferation, and induce anchorage-independent growth [9]. The special interest of this review is the mechanism of transcriptional repression of cell cycle inhibitors by c-Myc.
Section snippets
C-Myc represses transcription of cell cycle arrest genes by two distinct mechanisms
The significance of negative regulation of cell cycle inhibitors by c-Myc was best described for c-Myc-mediated repression of TGF-β-induced growth arrest. Transforming growth factor-β (TGF-β) is a potent growth inhibitor of various cell types, causing growth arrest in G1 (for reviews, see [10], [11]). It must downregulate c-Myc expression in order to stimulate cell cycle arrest and prevent cell proliferation. At the same time, the loss of response to TGF-β-induced growth arrest is often linked
Conclusions
Abnormal Myc expression results in oncogenic activation and contributes to the progression of a variety of tumors. Experiments with c-Myc null cells showed that growth arrest genes p15 [21], p27 [31], and gadd45 [37] were upregulated in these cells relative to parental cells. Likewise, p21 transcription was downregulated in c-Myc overexpressing cells [29]. These data suggest that growth arrest genes are targets of c-Myc repression in vivo. The ability of c-Myc to repress transcription of
Acknowledgements
We thank Robert Streit for editorial assistance. A. L. G. research is supported by CRB and IDPH Penny Severns Breast and Cervical Cancer Grants.
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Present address: UCSF, Comprehensive Cancer Center, San Francisco, CA 94115, USA.