CELL CYCLE AND ITS REGULATIONS

CELL CYCLE AND ITS REGULATIONSByBANSIL HIRPARA-15BBT0052PRIYANSHU GUPTA-15BBT0148

Overview of the Cell Cycle and Its Control

Two fundamental processes occur with each cell cycle--chromosomes replicate, and then they segregate equally to two daughter cells. The mechanisms by which these processes occur are similar in all eukaryotic cells. Processes occurring during the cell cycle are highly regulated and coordinated. The cell cycle is regulated primarily at the DNA replication and mitosis steps.

The master controllers of the cell cycle are 1) heterodimeric protein kinases composed of a regulatory subunit (a cyclin) and a catalytic subunit (a cyclin-dependent kinase, CDK), 2) two ubiquitin-protein ligases, and 3) regulatory phosphatases. Cyclin-CDKs phosphorylate and thereby regulate the activities of numerous cell proteins that participate in replication and division. The bound cyclins regulate the activities of the CDKs. Ubiquitin-protein ligases participate in the timed destruction of cyclins and other key proteins and thereby ensure passage through the cell cycle is irreversible. In the absence of regulation, cells replicate and divide uncontrollably, leading to diseases such as cancer.

CELL CYCLE

A cell reproduces by performing an orderly sequence of events in which it duplicates its contents and then divides in two.

The phases of cell cycle

Embryonic cell cycle and somatic cell cycle

External Factors that can Influence Cell Division

Chemical factors-Lack of nutrients inhibit cell divisionPresence of specific growth factors are needed for cell divisionPlatelet-derived Growth Factor (PDGF) is required for division of fibroblasts used in healing Receptors on plasma membrane bind PDGF and trigger pathway to signal cell division

Physical factors-Density-dependent inhibitionCell division limited by quantities of nutrients and growth regulatorsAnchorage-dependent inhibitionCells must attach to substratum (surface)Anchorage is signaled to cell-cycle control system by linkage between membrane proteins and elements of cytoskeleton

The cell-cycle control system

Operates like a timer that triggers the events in a set sequenceThe system of switches is binary (ON/OFF) and launches events in a complete, irreversible fashionThe control system is independent of the events it controlsThe system is highly adaptable and can be modified to suit specific cell types

The Cyclin-Cdk complexes: the major components of the cell cycle control system

Cyclically activated protein kinases control cell cycle progressionCyclin-dependent kinases (Cdks)The gosystem (or the engine)Expression is constant through the cell cycleKinases activity oscillates in the cell cycleCyclical changes in Cdk activity are controlled by an array of enzymes and other proteinsAmong these, cyclins are the major molecules

THE CYCLINS

Four classes of cyclins:G1-cyclinshelp to promote passage through Startor the restriction point in late G1 G1/S-cyclinsbind Cdks at the end of G1 and commit the cell to DNA replication S-cyclinsbinds Cdks during S phase and are required for the initiation of DNA replication M-cyclinspromote the events of mitosis

The major Cyclin-CDK complexes

Mechanism of Cell Cycle Regulation

The initiation of the cell cycle occurs with the receipt of a signal (e.g., a growth factor ligand) by a cell in G0 or G1. The signal induces synthesis of G1 and G1/S phase cyclin-CDKs, which then activate transcription of genes encoding DNA synthesis enzymes and S phase cyclin-CDKs. S phase cyclin-CDKs initially are held in check by inhibitors until G1/S phase cyclin-CDKs phosphorylate the inhibitors. This triggers their polyubiquitination by SCF ubiquitin ligase and degradation by proteasomes. The released S phase cyclin-CDKs then phosphorylate regulatory proteins bound to chromosomal replication origins, promoting initiation of DNA synthesis. The synthesis of mitotic cyclin-CDKs increases in S and G2 phases.

The activities of these complexes initially are blocked by phosphorylation of CDK subunits, and then are activated later by dephosphorylation. Once activated, mitotic cyclin-CDKs phosphorylate a large number of proteins that control chromosome condensation, retraction of the nuclear envelop, formation of the mitotic spindle, and alignment of chromosomes at the metaphase plate.

Subsequently, the anaphase promoting complex (APC/C), another ubiquitin ligase, polyubiquitinates a protein called securin which helps hold the sister chromatids of metaphase chromosomes together. The degradation of securin by proteasomes initiates anaphase and sister chromatids separate. Later in anaphase, APC/C polyubiquitinates mitotic cyclins leading to their degradation. Due to the loss of mitotic cyclin-CDK kinase activity proteins responsible for chromosomal condensation, etc. are dephosphorylated. Chromosomes then decondense, and nuclear membranes are re-synthesized. Cells next move forward into telophase where cytokinesis occurs, completing the cell cycle.

. In the ensuing G1 phase, replication origin regulators are synthesized and pre-replication complexes assemble at origins. This prepares cells for another round of DNA synthesis in the next S phase. Due to degradation of regulatory proteins at the G1/S, metaphase/anaphase, and anaphase/telophase boundaries, the passage of cells through the cell cycle is irreversible. The G1/S transition (START) is a major checkpoint after which passage through the cycle becomes independent of mitogens (e.g., growth factors).