Cancer periods: interphase—during which the cell grows, accumulating
Cancer and cell cycle control: The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication (replication).
In cells without a nucleus (prokaryotic), the cell cycle occurs via a process termed binary fission. In cells with a nucleus (eukaryotes), the cell cycle can be divided in two brief periods: interphase—during which the cell grows, accumulating nutrients needed for mitosis and duplicating its DNA—and the mitosis (M) phase, during which the cell splits itself into two distinct cells, often called “daughter cells”.The cell-division cycle is a vital process by which a single-celled fertilized egg develops into a mature organism, as well as the process by which hair, skin, blood cells, and some internal organs are renewed. Key molecules within the cancer cell cycle control system: CDKs CDKs – cyclin dependent kinases.
The activity of CDKs rises and falls as the cell progresses through the cycle. Oscillation leads to cyclical changes in the phosphorylation of proteins that regulate major events in the cell cycle. DNA replication, mitosis, chromosome condensation etc.
Key molecules (2): Cyclins Cyclines are CDK regulators.Unless tightly bound to a cyclin CDKs have no protein kinase activity. Cycles of synthesis and degradation hence the name. CDK levels remain constant. Cyclical changes in cyclin levels result in cyclic assembly and activation of the cyclin-CDK complexes. This activation triggers cell-cycle events.
Cellcyclecontrol/ inhibitors: Two families of genes, the cip/kip family and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors.The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53 (which, in turn, is triggered by DNA damage e. g.
due to radiation). p27 is activated by Transforming Growth Factor ? (TGF ? ), a growth inhibitor. The INK4a/ARF family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14arf which prevents p53 degradation. Synthetic inhibitors of Cdc25 could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.
Cyclin-CDK complex Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell’s progress through the cell cycle. Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination.Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome.
Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell’s genome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die.However, for reasons related to gene copy number effects, possession of extra copies of certain genes is also deleterious to the daughter cells.
Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore.APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed. Interphase: Interphase generally lasts at least 12 to 24 hours in mammalian tissue. During this period, the cell is constantly synthesizing RNA, producing protein and growing in size. By studying molecular events in cells, scientists have determined that interphase can be divided into 4 steps: Gap 0 (G0), Gap 1 (G1), S (synthesis) phase, Gap 2 (G2).
The cell cycle control depends on proteolysis Cyclin-CDK complexes inactivated by proteolysis of cyclins.Cyclin destruction occurs by a ubiquitin-dependent mechanism. Proteins marked for destruction by the covalent attachment of multiple copies of a small protein called ubiquitin. The rate limiting step in cyclin destruction is the final ubiquitin-transfer reaction catalyzed by ubiquitin ligases.
The cell cycle control depends on proteolysis (2) •In G1 and S phases an enzyme complex SCF responsible for the ubiquitylation and destruction of G1/S cyclins •In M phase, the anaphase promoting complex (APC) is responsible for the ubiquitylation and proteolysis of M-cyclins