CANCER AND SIGNALLING PTHWAY ACTIVATION
The consequence of signalling pathway activation by growth factors and mitogens is, of course, the initiation of cell proliferation. Activated receptors propagate primary mitogenic signals, triggering the transition from Go into G1 (Fig. 1).
1.Biochemical events during proliferation in eukaryotic cells.
Irrespective of cell type, the primary signals generate three responses that occur in parallel: (1) metabolic activation, characterised by increased uptake of essential precursors for RNA and protein synthesis and of glucose to produce adenosine-5′-triphosphate (ATP); (2) activation of RNA and protein synthesis; and (3) activation of a programme of gene expression that begins with the ‘immediate early response genes’ within the first few hours. Central to cell proliferation among these genes is MYC, the expression of which on by a variety of growth factors that activate RTKs.
MYC is essential for normal cell proliferation and high levels of expression accelerate growth, is not expressed in dividing germ cells. MYC is a transcription factor that regulates the expression of ~15% of human genes and it may, therefore, be considered a ‘master’ cell regulator. The MYC protein family (MYC, MYCN and MYCL) each contain basic helix–loop–helix and leucine zipper domains that characterise a major class of transcription factors (Fig. 2).
2.Structure of MYC and MAX.
Each forms heterodimers with the protein MAX (which also contains all three motifs) that bind specifically to DNA as trans-activating complexes (i.e. complexes that activate the transcription of other genes). MAX expression is independent of MYC and MAX may thus regulate gene transcription independently of MYC. Other leucine zipper proteins (the MDX family, MLX, MXI1 and MNT) form heterodimers with MAX that represses transcription, giving rise to a complex regulatory network.
MYC exerts a dominant role in cell proliferation through its capacity to trans-activate a number of key cell cycle genes, notably cyclin D1 (CCND1) and CDC25A. Cyclin D1 controls progression through G1 and into the S phase of the cell cycle in which the genomic content of DNA is duplicated. CDC25A is a critical regulator of progression into the mitotic phase and its expression pattern during the cell cycle closely resembles that of MYC. It is also aberrantly expressed in some types of cancer and it is easy to see how abnormal regulation of a key step in the cycle could contribute to uncontrolled proliferation. MYC also regulates all three RNA polymerases and thus exerts an indirect effect on the transcriptional expression of the entire genome. In addition to these actions as a transcription factor, MYC plays a direct role in DNA replication by interacting with the pre-replicative complex. Consistent with these central roles in cell division and the duplication of DNA, MYC is repressed when cell growth is arrested, for example, in response to DNA damage.
The importance of MYC in regulating key cellular processes suggests that control of its expression is critical. Normal MYC abundance is indeed regulated by the rate of transcription into mRNA and by the stability of both its mRNA and of MYC protein itself. The de-regulation of MYC expression in cancers can also occur via multiple mechanisms (Fig. 3).
3. Mechanisms regulating MYC expression.
Normal MYC undergoes ubiquitin-mediated proteolysis, which confers a short half-life (~20 minutes). A number of mutations, arising for example in Burkitt’s lymphoma, inhibit this degradative pathway and substantially increase the lifetime of MYC. Amplification and/or over-expression of MYC commonly occurs in a wide range of tumours. Mutations in the protein sequence are not necessary to render MYC oncogenic although when they do occur they may enhance its tumour-promoting capacity.