CELL CYCLE REGULATION AND CANCER Cellular Reproduction II
THE CELL CYCLE Interphase G1- gap phase 1- cell grows and develops S- DNA synthesis phase- cell replicates each chromosome G2- gap phase 2- cell prepares for cell division and duplicates organelles G0- resting (no cell division) Mitosis Prophase- chromosomes condense and nuclear membrane dissolves Metaphase- chromosomes align on the metaphase plate Anaphase-spindle fibers separate chromosomes Telophase-nuclear membrane reforms around the separated chromosomes Cytokinesis- cell divides
CELL CYCLE REGULATORS Stimulators Protein molecules that regulate the cell cycle by stimulating the cell to move on to the next step in the cycle. Inhibitors Protein molecules that regulate the cell cycle by inhibiting the cell from going on to the next stage of the cycle. Coded for by protooncogenes Coded for by tumor suppressor genes
STIMULATORS When proto-oncogenes become mutated they are called oncogenes (onco=tumor) A mutation in one of these genes stimulates the cell cycle to continue regardless of errors. And is therefore considered a dominant mutation. You only have to have one mutated copy to see its affect. Examples of stimulators: CDK- cyclin dependent kinases Cyclins- proteins that change concentration during the cell cycle phases and regulate the flow through the cell cycle Growth factors- molecules that cause cells to divide APC- anaphase promoting complex- these molecules destroy the proteins in the centromere that holds chromosomes together allowing them to separate in anaphase.
INHIBITORS When tumor suppressor genes become mutated they can no longer suppress or inhibit the cell cycle. Mutated tumor suppressor genes are considered recessive because you must have two copies of it to see it s affect. Examples of Inhibitors: P53- gene that inhibits cell division by activating DNA repair molecules or initiated apoptosis BRCA1- breast cancer 1- gene that repairs broken DNA ATM- ataxia telangiectasia mutated- halts the cell cycle and activates repair molecules Rb- Retinoblastoma protein- prevents cells from entering S phase, CDK-cyclins phosphorylate Rb to allow cells to enter S phase MAD- mitotic arrest deficient- inhibit APC and stops anaphase from occurring
G1/S CHECKPOINT Checks for: DNA Damage Sufficient Resources If check point is passed the cell can: Proceed to S phase CDK-cyclin D and E present If the cell does not pass: Apoptosis- cell death G 0 - resting/non-dividing (cyclin C) P53 or Rb present G 0 - metabolically active cells that are fully differentiated, cells that are waiting for available resources or favorable conditions. Stage of development Type of cell Available resources
S CHECKPOINT Checks for: Errors in DNA replication If check point is passed the cell can: Proceed to G2 CDK-cyclin A and E present proceed to G2 If the cell does not pass: Repair the errors If errors can t be repaired, apoptosis ATM or BRCA1 present
G2/M CHECKPOINT Checks for: DNA Damage Complete pairs of chromosomes Enough cell components If check point is passed the cell can: Proceed to M CDK-cyclin A and B present If the cell does not pass: Repair the errors If errors can t be repaired, apoptosis p53 present
M CHECKPOINT Checks for: All chromosomes attached to mitotic spindle If check point is passed the cell can: Proceed to Anaphase CDK-cyclin B present APC/C Present proceed to anaphase If the cell does not pass: Repair the errors If errors can t be repaired, apoptosis MAD present halts mitosis
COLON CANCER Colon cancer is the 3 rd most common form of cancer in men and women. Mutations that cause colon cancer can be inherited or newly acquired. Inherited colon cancer is called familial adenomatous polyposis and is a result of a mutation to the APC gene. Cells of the colon must constantly be replaced and therefore go through the cell cycle frequently. When a mutation occurs in the stem cells of the villi of the colon the cells that differentiate from that stem cell carry the mutation. When there is a mutation in the APC gene, the APC protein does not direct proper cell differentiation and underdeveloped villi cells build up forming an adenoma (benign tumor). When cells divide in an uncontrolled manner mutational rates (mistakes) increase. Most cancers are a result of many mutations. If P53 becomes mutated the cells continue to proliferate become carcinoma or a cancer.
APC AND P53 P53 Located on chromosome 17 Tumor suppressor gene (when mutated it cannot inhibit cell division) Half of colon cancers show a mutation in p53. Regulates cell division and keeps cells from dividing too fast.-guardian of the genome. APC Located on chromosome 5 Proto-oncogene (when mutated it becomes an oncogene) More than 300 mutations have been identified in APC that cause colon cancer. It helps control how often a cell divides, how it attaches to other cells within a tissue, and whether a cell moves within or away from a tissue. This protein also helps ensure that the number of chromosomes in a cell is correct following cell division.
BREAST CANCER Breast cancer is the most common cancer in American women. About 1 in 8 women will develop some form of breast cancer in their lifetime. 5-10% of all breast cancers are hereditary and result from mutations in the BRCA1 and BRCA2 genes. Mutated BRCA1 protein can not properly repair DNA. DNA damage builds up and the cells proliferate becoming a breast adenoma. If another tumor suppressor gene gets damaged by the lack of DNA repair function, such as p53, the cells will become a carcinoma
BRCA1 A tumor suppressor gene located on chromosome 17. There are over 1000 identified mutations in this gene that have been shown to cause or increase the risks of breast cancer. Normal BRCA1 protein is a key molecule for DNA repair. The protein mends broken DNA. Mutated BRCA1 protein can not properly repair DNA. DNA damage build up and the cells proliferate becoming a breast adenoma. If another tumor suppressor gene gets damaged by the lack of DNA repair function, such as p53, the cells will become a carcinoma.