SIG - Regulation of the Cell Cycle [LESSON]

Regulation of the Cell Cycle

The purpose of cell division is growth, repair, and the replacement of aging cells. However, mitosis occurs at different rates for different cells, depending on their location and function in the organism. Some tissues will need more growth or repair than others, such as bone cells in a growing child. There is a molecular control system that regulates the rate of cell division for the various types of cells. In this lesson, you will learn about the various mechanisms and molecules used by this control system. You will also examine what happens when mistakes occur within this control system and uncontrolled cell division occurs. 

Positive controls

Cyclins are among the most important core cell cycle regulators. Cyclins are a group of related proteins, and there are four basic types found in humans and most other eukaryotes. As the name suggests, each cyclin is associated with a particular phase, transition, or set of phases in the cell cycle and helps drive the events of that phase or period. A typical cyclin is present at low levels for most of the cycle, but increases strongly at the stage where it's needed. M cyclin, for example, peaks dramatically at the transition from G2 to M phase. G1 cyclins are unusual in that they are needed for much of the cell cycle.

 A typical cyclin is present at low levels for most of the cycle, but increases strongly at the stage where it's needed.

In order to drive the cell cycle forward, a cyclin must activate or inactivate many target proteins inside of the cell. Cyclins drive the events of the cell cycle by partnering with a family of enzymes called the cyclin-dependent kinases (Cdks). A lone Cdk is inactive, but the binding of a cyclin activates it, making it a functional enzyme and allowing it to modify target proteins.

How does this work? Cdks are kinases, enzymes that phosphorylate (attach phosphate groups to) specific target proteins. The attached phosphate group acts like a switch, making the target protein more or less active. When a cyclin attaches to a Cdk, it has two important effects: it activates the Cdk as a kinase, but it also directs the Cdk to a specific set of target proteins, ones appropriate to the cell cycle period controlled by the cyclin.

Image shows that without cyclin CDK is inactive and the target cells are not phosphorylated so the S phase cannot begin.

A famous example of how cyclins and Cdks work together to control cell cycle transitions is that of maturation-promoting factor (MPF). MPF provides a good example of how cyclins and Cdks can work together to drive a cell cycle transition. Like a typical cyclin, M cyclin stays at low levels for much of the cell cycle, but builds up as the cell approaches the G2/M transition. As M cyclin accumulates, it binds to Cdks already present in the cell, forming complexes that are poised to trigger M phase. Once these complexes receive an additional signal (essentially, an all-clear confirming that the cell’s DNA is intact), they become active and set the events of M phase in motion. MPFs phosphorylate many different proteins that are needed to condense DNA, break down the nuclear membrane, and help the cell enter mitosis.

Negative controls

Negative regulators of the cell cycle may be less active (or even nonfunctional) in cancer cells. For instance, a protein that halts cell cycle progression in response to DNA damage may no longer sense damage or trigger a response. Genes that normally block cell cycle progression are known as tumor suppressors.

As an example, let's examine how DNA damage halts the cell cycle in G1. DNA damage can, and will, happen in many cells of the body during a person’s lifetime (for example, due to UV rays from the sun). Cells must be able to deal with this damage, fixing it if possible and preventing cell division if not. Key to the DNA damage response is a protein called p53. p53 works on multiple levels to ensure that cells do not pass on their damaged DNA through cell division. First, it stops the cell cycle at the G1 checkpoint by triggering production of Cdk inhibitor (CKI) proteins. The CKI proteins bind to Cdk-cyclin complexes and block their activity (see diagram below), buying time for DNA repair. p53's second job is to activate DNA repair enzymes. If DNA damage is not fixable, p53 will play its third and final role: triggering programmed cell death so damaged DNA is not passed on.

First, it stops the cell cycle at the G1 checkpoint by triggering production of Cdk inhibitor (CKI) proteins.

By ensuring that cells don't divide when their DNA is damaged, p53 prevents mutations (changes in DNA) from being passed on to daughter cells. When p53 is defective or missing, mutations can accumulate quickly, potentially leading to cancer. Indeed, out of all the entire human genome, p53 is the single gene most often mutated in cancers.

Cancer

Cancer is basically a disease of uncontrolled cell division. Its development and progression are usually linked to a series of changes in the activity of cell cycle regulators. For example, inhibitors of the cell cycle keep cells from dividing when conditions aren’t right, so too little activity of these inhibitors can promote cancer. Similarly, positive regulators of cell division can lead to cancer if they are too active. In most cases, these changes in activity are due to mutations in the genes that encode cell cycle regulator proteins.  Here are just a few ways that cancer cells behave differently.

For example, cancer cells can multiply in culture (outside of the body in a dish) without any growth factors, or growth-stimulating protein signals, being added. This is different from normal cells, which need growth factors to grow in culture. Cancer cells may make their own growth factors, have growth factor pathways that are stuck in the "on" position, or, in the context of the body, even trick neighboring cells into producing growth factors to sustain them. Cancer cells also ignore signals that should cause them to stop dividing. For instance, when normal cells grown in a dish are crowded by neighbors on all sides, they will no longer divide. Cancer cells, in contrast, keep dividing and pile on top of each other in lumpy layers (tumor).

Cancer cells can often spread (metastasize) to other parts of the body and they can also avoid programmed cell death (apoptosis).  Remember that normal cells will trigger apoptosis if there is anything amiss, but cancer cells have mechanisms to avoid this.  Cancer is so incredibly difficult to treat because of all the complex signaling pathways – we have to target human cells but avoid killing healthy cells.  Right now, chemotherapy is used to prevent cells from dividing, but that means healthy hair cells, intestinal cells, and other cell types can’t divide while a patient is receiving treatment.  Therefore, chemotherapy has a lot of severe side effects such as hair loss and intense nausea and vomiting.

Complete the question-and-answer Regulation interactive below to check your knowledge. 

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