Regulation of the Cell Cycle

How does a cell know when to divide and when not to divide?

Regulation of the Cell Cycle Internal and external factors regulate cell division. External factors – factors or signals that come from the outside of the cell that help to control the division process Internal factors – factors or signals from the inside of the cell that control the division process

External Factors Cell to Cell contact Growth Factors Platelets Erythropoeitin Hormones

Cell to Cell Contact Once a cell touches other cells it stops dividing. The exact reason is considered a phenomenon and is unknown. One hypothesis suggests that receptors on neighboring cells bind to each other and trigger the cytoskeleton to block signals that will trigger growth.

External signals Growth factors coordination between cells protein signals released by body cells that stimulate other cells to divide density-dependent inhibition crowded cells stop dividing each cell binds a bit of growth factor not enough activator left to trigger division in any one cell anchorage dependence to divide cells must be attached to a substrate “touch sensor” receptors

Growth Factors Growth factors are a broad group of proteins that act as chemical signals released from other cells to tell other cells to divide. Growth factors bind to receptors that activate specific genes to trigger cell growth. Cells will usually respond to a combination of several growth factors not just one.

Examples Platelets-form clots to stop bleeding and carry growth factors that helps your body repair wounds by signaling certain cells to divide.

Erythropoietin-stimulates the production of red blood cells and becomes present when oxygen levels are depleted.

Hormones Hormones stimulate the growth of certain cell types. Ex. Growth hormone results in bone growth and also affects metabolism.

Internal Factors Enzymes Kinases Cyclins

Apoptosis Just as some cells need to divide, some cells need to die. Apoptosis is programmed cell death. Internal or external factors stimulate genes that activate self destructive enzymes. The cell will then be recognized and ingested by immune system cells.

Kinases and Cyclins Kinases are enzymes that when activated transfer a phosphate group from one molecule to a target molecule. This gives energy or changes the shape of the target molecule. Some kinases help control the cell cycle. Cyclins are proteins that are rapidly made and broken down that activate kinases.

Cell cycle controls cyclins Cdks Cdk-cyclin complex regulatory proteins levels cycle in the cell Cdks cyclin-dependent kinases phosphorylates cellular proteins activates or inactivates proteins Cdk-cyclin complex triggers passage through different stages of cell cycle

Cyclins & Cdks Interaction of Cdk’s & different cyclins triggers the stages of the cell cycle Leland H. Hartwell checkpoints Tim Hunt Cdks Sir Paul Nurse cyclins

Spindle checkpoint G2 / M checkpoint M cytokinesis C G2 mitosis G1 S Chromosomes attached at metaphase plate Replication completed DNA integrity Inactive Active Active Inactive Cdk / G2 cyclin (MPF) M APC cytokinesis C G2 mitosis G1 S Cdk / G1 cyclin Inactive MPF = Mitosis Promoting Factor APC = Anaphase Promoting Complex Active G1 / S checkpoint Growth factors Nutritional state of cell Size of cell

Cyclin & Cyclin-dependent kinases CDKs & cyclin drive cell from one phase to next in cell cycle proper regulation of cell cycle is so key to life that the genes for these regulatory proteins have been highly conserved through evolution the genes are basically the same in yeast, insects, plants & animals (including humans)

Growth factor signals growth factor cell division cell surface nuclear pore nuclear membrane P P cell division cell surface receptor Cdk protein kinase cascade P E2F P chromosome Rb P E2F cytoplasm Rb nucleus

Example of a Growth Factor Platelet Derived Growth Factor (PDGF) made by platelets in blood clots binding of PDGF to cell receptors stimulates cell division in connective tissue heal wounds Don’t forget to mention erythropoietin! (EPO)

Growth Factors and Cancer Growth factors can create cancers proto-oncogenes normally activates cell division growth factor genes become oncogenes (cancer-causing) when mutated if switched “ON” can cause cancer example: RAS (activates cyclins) tumor-suppressor genes normally inhibits cell division if switched “OFF” can cause cancer example: p53

What happens when cell division becomes uncontrolled?

Cancer Cancer is a common or generic name given to diseases that are characterized by uncontrolled cell division. Cancer cell will continue to divide without the presence of growth factors and will also continue to divide when in contact with other cells. Cancer cells divide much more than healthy cells.

Tumors When clumps of cancer cells form they are called tumors. Two types: Benign Malignant

Benign Tumors Benign tumors usually remain localized and do not spread. Usually harmless and may be cured simply by removal.

Dermatofibroma

Benign Tumor Image

Malignant Tumor In a malignant tumor certain cells may break away from the tumor and spread. When cancerous cells spread, we say that they metastasize. Done by entering the blood and lymp vessels of the circulatory system where they invade other areas and form new tumors. Tumors are difficult to eradicate once they metastasize.

Right lung is healthy, the left lung is not.

Skin Cancer

Why are tumors harmful?

Cancer Cells Tumors Cancer cells don’t perform the specialized functions needed by the body. The body has large volumes of rapidly dividing cells that require lots of blood and energy but pose no usefulness to the body. Tumors can exert pressure on vital organs when they become too large.

Where do cancer cells come from?

Cancer cells will usually come from normal cells that have suffered damage to their genes (mutations) that are associated with making proteins that regulate the cell cycle. Oncogenes are one type that will accelerate cell growth. Other genes act as cell cycle brakes.

Inheritance Mutations in various genes can be inherited (e.g. breast cancer).

Other mutations can also be caused by exposure to different chemicals or radiation (e.g skin cancer).

UV Radiation

Carcinogens are substances that may cause mutation.

Carcinogens cont…tobacco

Carcinogens…asbestos Carcinogens are substances that may cause mutation (e.g. tobacco smoke, air pollutants, asbestos).

Carcinogens….air pollutants.

Viruses Some oncogenes may be carried by a virus and cause cancer (e.g. cervical cancer often results from the Human papilloma virus - HPV). The HIV virus leaves the body more susceptible to cancer.

Radiation Localized treatment that damages a cell’s DNA and prevents it from dividing

Chemotherapy Drugs that kill actively dividing cells. May kill healthy cells.

Cancer Treatment More effective treatments may include a combination of both chemotherapy and radiation.