10.4 Cancer and the cell cycle

Cancer comprises many different diseases caused by a common mechanism: uncontrolled cell growth. Despite the redundancy and overlapping levels of cell cycle control, errors do occur. One of the critical processes monitored by the cell cycle checkpoint surveillance mechanism is the proper replication of DNA during the S phase. Even when all of the cell cycle controls are fully functional, a small percentage of replication errors (mutations) will be passed on to the daughter cells. If changes to the DNA nucleotide sequence occur within a coding portion of a gene and are not corrected, a gene mutation results. All cancers start when a gene mutation gives rise to a faulty protein that plays a key role in cell reproduction. The change in the cell that results from the malformed protein may be minor: perhaps a slight delay in the binding of Cdk to cyclin or an Rb protein that detaches from its target DNA while still phosphorylated. Even minor mistakes, however, may allow subsequent mistakes to occur more readily. Over and over, small uncorrected errors are passed from the parent cell to the daughter cells and amplified as each generation produces more non-functional proteins from uncorrected DNA damage. Eventually, the pace of the cell cycle speeds up as the effectiveness of the control and repair mechanisms decreases. Uncontrolled growth of the mutated cells outpaces the growth of normal cells in the area, and a tumor (“-oma”) can result.

Proto-oncogenes

The genes that code for the positive cell cycle regulators are called proto-oncogenes . Proto-oncogenes are normal genes that, when mutated in certain ways, become oncogenes , genes that cause a cell to become cancerous. Consider what might happen to the cell cycle in a cell with a recently acquired oncogene. In most instances, the alteration of the DNA sequence will result in a less functional (or non-functional) protein. The result is detrimental to the cell and will likely prevent the cell from completing the cell cycle; however, the organism is not harmed because the mutation will not be carried forward. If a cell cannot reproduce, the mutation is not propagated and the damage is minimal. Occasionally, however, a gene mutation causes a change that increases the activity of a positive regulator. For example, a mutation that allows Cdk to be activated without being partnered with cyclin could push the cell cycle past a checkpoint before all of the required conditions are met. If the resulting daughter cells are too damaged to undergo further cell divisions, the mutation would not be propagated and no harm would come to the organism. However, if the atypical daughter cells are able to undergo further cell divisions, subsequent generations of cells will probably accumulate even more mutations, some possibly in additional genes that regulate the cell cycle.