The cell cycle (Figure 64.1)

When a cell is instructed to divide by an extracellular growth signal it enters into the cell cycle. The events are divided into four phases.

• G1 phase: cells will check the environment to ensure sufficient nutrients are available to sustain growth. They also check the integrity of the DNA molecules for any damage. There is a specific point, the restriction point or R point, through which a cell will not pass if DNA damage is detected.
  
• S phase: the DNA present in the chromosomes is replicated.
  
• G2 phase: the integrity of the replicated DNA is checked and the cell prepares for mitosis.
  
• M phase: in the mitotic phase chromosomes condense and the cell divides to produce two daughter cells each containing a faithful copy of the parental DNA.

Oncogenes

RNA tumour viruses can cause cancer in humans. Two broad classes of RNA tumour virus exist: acute acting, originally called sarcoma viruses, and those that act in a chronic manner, called leukaemia viruses. They have an RNA genome that is reverse transcribed by RNA-dependent DNA polymerase (Figure 64.2a) into a proviral double-stranded DNA molecule that integrates into a host chromosome after the virus infects a host cell. New virus components are synthesised and new virus particles assemble at the cell membrane and bud from the host cell, thus the host cell is not lysed by new viral growth.

The RNA virus genome contains genes essential for growth. The genes are called gag, pol, and env genes (Figure 64.2b). The gag gene codes for the core viral proteins (‘gag’ actually stands for ‘group-specific antigen’. The viruses were identified using antibodies to detect the core proteins and divided into groups according to which antibodies detected them). The ‘pol’ gene codes for the viral-specific reverse transcriptase enzyme and the ‘env’ gene codes for the viral envelope proteins. Sarcoma viruses were also found to contain another gene, called ‘src’ for sarcoma gene. This gene is known as an oncogene as it can be responsible for initiating the cell transformation process.

Different viral oncogenes are present in different sarcoma viruses. Surprisingly, genes similar to these are found in our human genome. They are termed proto-oncogenes and are usually silent in differentiated cells. Cells infected by sarcoma virus produce viral oncoproteins that initiate cancer cell formation. However, cell transformation can also be initiated by the presence of a leukaemia-type RNA tumour virus. If the replicated DNA copy of an RNA viral genome integrates next to a silent host oncogene it can cause it to be overexpressed. The reverse transcription process generates identical sequences at both ends of the proviral DNA not originally present in the viral RNA, called long terminal repeats (LTRs). These sequences contain elements that promote transcription, i.e. strong promoter regions and enhancer regions.

There are many different types of oncogene now known, coding for a variety of different gene products; they can activate cell division or inhibit apoptosis (Figure 64.3). The different types of gene product can be divided into five major groups.

• extracellular growth signals, e.g. v-sis gene product from the Simian sarcoma virus mimics platelet-derived growth factor;
  
• growth factor receptors, e.g. the v-erb B gene product from the erythroblastosis virus mimics the epidermal growth factor receptor, except that it acts as if a ligand is constantly bound;
  
• G protein-like, e.g. ras (rat sarcoma) oncogene product. One of the first oncogenes to be discovered in humans. When stimulated, G proteins become active by binding GTP. This is immediately broken down by a GTPase activity, present in the protein, to limit the signal. Point mutations in many oncogene products of this type result in the loss of GTPase and hence the growth signal is always on;
  
• transcription factors, several oncogene products mimic transcription factors and switch on growth genes;
  
• cancer may result from the absence of cell death. Alteration of gene expression involved in programmed cell death, apoptosis, will lead to excess cell mass, e.g. overexpression of bcl-2 or mutation of bax genes can alter apoptosis.