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In this chapter we will have a closer look at the early cell cycle arrest in G1-phase, which can have a number of causes depending on the incoming signals. Let´s again analyze the CDK4 reaction. Press the button in the first figure. CDK4/6 form a complex with cyclin D in the presence of p27kip1. This kinase now phosphorylates and inactivates the retinoblastoma protein pRb resulting in cyclin E expression through release of factors important for transcription.

Lack of cyclin D1 causes lack of CDK4/6 activity and thus pRb cannot be phosphorylated. This results in lack of cyclin E expression and inhibition of CDK2 activity. The excess p27 from CDK4/6, which is unable to bind this kinase because of missing cyclin D1 can now bind to cyclin E-CDK2. This mechanism is shown in a previous section (about CDK´s). Another mechanism is the expression of the CDK4/6 inhibitor p16ink4, which competes with cyclin D1 for binding to CDK4/6 and inhibits this crucial kinase leading to cell cycle arrest.

Regulation in Cancer Cells

Cancer cells have developed a number of mechanism to overcome checkpoint control. One mechanism is the overproduction of cyclin D1 as shown in the animation on your right. The increased level of cyclin D1 pushes the complex formation with CDK4/6. CDK4/6 overexpression has also been observed and would have a similar effect making sure that complex formation is favoured. Mechanisms leading to lack of expression of CDK4/6 or cyclin D as observed in normal cells are thus eliminated.

Very frequently mutated pRb (retinoblastoma protein) is found in many cancers (mutated or missing pRb protein; remember: both gene copies are affected). Lack or mutant pRb causes the transcription factor E2F to be free and E2F will transcribe important genes for S-phase including cyclin E. CDK4/6 are useless in this case since pRb seems to be the only protein which is phosphorylated by these kinases. Thus the pRb checkpoint is bypassed (Check the animation on your right). Lack of p16 is another frequently observed mutational event. In this case either p16 or pRb are missing but never both at the same time except in hormone-independent prostate cancer, where both can be missing simultaneously.

These examples show that in cancer cells the first checkpoint is primarily inactivated. Cells usually arrest at this checkpoint due to natural causes such as growth factor removal etc. However, even if p16 is missing, cells can still arrest at the first checkpoint by other means such as lack of cyclin D1 or expression of other ink (p16-like) proteins. Most probably for the natural environment in the body in which the cancer grew up this was a suitable way to overcome growth restraint. Cancers derived from different organs show certain non-random patterns of mutations.

What comes next? In the next chapter we will get aquainted with another tumor suppressor protein, the p53 protein and its involvement in cell cycle arrest by gamma-irradiation.