Cell cycle cancer defects

In concordance with the central role of ubiquitin modification in multiple cellular functions perturbations of this system are associated with a variety of diseases. Defects in the control of cell cycle regulators by the ubiquitin proteasome system are connected to cancer progression and many E3 ligases were originally identified as oncogenes. 

Cancer results from a disruption of the normal regulation of the cell cycle. When the cycle proceeds without control, cells can divide without order and accumulate genetic defects that can lead to a cancerous tumor. 

After having discussed the cell-cycle transitions and the major steps in cytokinesis, the controls, (checkpoints) that watch over cell-cycle transitions and arrest the cycle when a defect has been spotted will be discussed. These cell-cycle checkpoints are of great importance. Malfunctions of these controls result in reduced fidelity of the timing of the cell cycle. They cause chromosomal instabilities (CINs) and result in uncontrolled cellular proliferation, and eventually cancer (see ref. 31 and Part 4). 

But even more important than the activation of oncogenes are defects in tumour-suppressor genes. This is hardly suiprising, considering the central role of tumour suppressors in the control of the cell cycle and cell death. In this case, mutations lead to a loss rather than a gain of function. The feet that, in most cases, a number of mutations must accumulate to transform a normal cell to a cancer cell shows how robust the signalling networks are. 

The DNA-damaging agent bleomycin arrests the cell cycle of Jurkat cells defective in the G1 checkpoint in the G2 phase, and microtubule-affecting colchicine arrests it in the M phase [40]. Boromycin showed no effect on the cell cycle status of Jurkat cells at least up to 340 nM but potentiated anti-tumor activity of bleomycin in SCID mice inoculated with Jurkat cells. These data suggest that boromycin disrupts the cell cycle at the G2 checkpoint of cancer cells selectively, leading to sensitization of cancer cells to anti-cancer reagents. 

Loss of function or dominant negative mutations in p53 have been found in a majority of human cancers. It is thought that the normal function of p53 is to cause cell-cycle arrest when DNA damage exists in cells about to enter S phase and undergo DNA replication. A defect in p53 function would allow damaged DNA to be replicated, which could result in profound genetic alterations. 

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