CELL CYCLE for ug and pg medical students for knowledge

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1. CELL CYCLE, IT’S CHECK POINT AND REGULATION Dr Shiwali Saharan 3rd year PG (O&G)

2. The cell cycle is an ordered series of events involving cell growth and cell division that produces two new daughter cells from one parent cell. Cells on the path to cell division proceed through a series of precisely timed and carefully regulated stages of growth, DNA replication, and nuclear and cytoplasmic division that ultimately produces two identical (clone) cells. The frequency of cell division varies depending on cell type and developmental stage.

3. For example, during embryogenesis, cells divide rapidly as the embryo grows in size. Conversely, in an adult human body, almost all cells are terminally differentiated and are not dividing (example: neurons) or divide very infrequently (example: liver cells that divide about once per year). These non-dividing cells are termed quiescent cells (They are in the Go stage ). There are some populations of adult human cells that are actively dividing. Examples of these include intestinal epithelial cells and adult-derived stem cells, such as bone marrow stem cells

4. PHASES OF CELL CYCLE Interphase : G1 (presynthetic phase) S (DNA synthesis) G2 (Pre-mitotic phase) M Phase : Mitosis Cytokinesis

5. G Phase (Resting Phase) Rb protein is in hypo-phosphorylated (active form). Hence, it holds the cell cycle at check point I by inhibitng the expression of transcription factors (E2F) that codes cyclins A & E necessary for cycle progression. Growth factor stimulation takes G cells to G 1 phase. Non proliferative cells in eukaryotes enter the quiescent G phase from G 1 and may remain quiescent for longer period of time (eg: cardiac cells). In multicellular eukaryotes, cells enter G from G 1 phase and stop dividing. Some cells enter the G phase semi-permanently (eg: liver, kidney cells).

6. G1 Phase (Gap) The first stage of interphase is called the G1 phase. D uring G1 stage, the cell is active at the biochemical level. The cell is accumulating the building blocks of chromosomal DNA and the associated proteins as well as sufficient energy reserves to complete the task of replicating each chromosome in the nucleus. Furthermore, during the G1 stage, DNA is assessed for damage and repaired, if needed and the cell also grows in size.

7. S Phase (Synthesis) Throughout interphase, nuclear DNA remains in a semi-condensed chromatin configuration. In the S phase, DNA replication result in the formation of identical pairs of DNA molecules—sister chromatids—that are firmly attached to the centromeric region. The centrosome is also duplicated during the S phase. The two centrosomes of homologous chromosomes will give rise to the mitotic spindle, the allows the movement of chromosomes during mitosis.

8. G2 Phase In the G2 phase, the cell replenishes its energy stores and synthesizes proteins necessary for chromosome manipulation and movement. Some cell organelles are duplicated, and the cytoskeleton is dismantled to provide resources for the mitotic phase. Like G1 stage, during G2, the size of the cell increases and DNA damaged is repaired, if needed. This phase has double number of chromosomes. The final preparations for the mitotic phase must be completed before the cell can enter the first stage of mitosis.

9. M Phase The mitotic phase (M-phase) is a multistep process during which the duplicated chromosomes are aligned, separated, and move into two new, identical daughter cells. M-phase has several sub-phases: P roph ase, M etaphase, A naphase, Telophase and Cytokinesis

10. Cytokinesis Cytokinesis is the second part of the mitotic phase during which cell division is completed by the physical separation of the cytoplasmic components into two daughter cells. In animal cells, cytokinesis begins following the onset of anaphase. A contractile ring composed of actin filaments forms just inside the plasma membrane at the former metaphase plate. The actin filaments pull the equator of the cell inward, forming a fissure. This fissure, or “crack,” is called the cleavage furrow. The furrow deepens as the actin ring contracts, and eventually, the membrane and cell are cleaved in two .

11. CELL CYCLE REGULATION

12. This restriction point is mainly controlled by the action of CKI-16 (CDK Inhibitor p16). The inhibited CDK dont bind with cyclin DI, hence there is no cell progression. Active cyclin D-cdk complexes phosphorylate retinoblastoma protein (Rb) in the nucleus. Unphosphorylated pRb acts as an inhibitor of G 1 by preventing E2F mediated transcription. Once pRb gets phosphorylated, E2f activates the transcription of cyclins E & A which then interacts with CDK2 to allow for G 1 S phase transition. This brings the cell to the end of the first checkpoint (unphosphorylated Rb inhibits E2F)

13. This restriction point is located at the end of G 2 phase. This checks the number of factors which are essential for cell division. Maturation promoting factor or mitosis or M phase promoting factor (MPF) is a protein composeof cyclin B and CDK-I. This protein promotes G 2 phase into entrance of M phase. MPF is activated at the end of G 2 by a phosphatase (Chk). The main functions of MPF here are: Triggers the formation of mitotic spindle promotes chromosome condensation causes nuclear breakdown. If there are any damages in this restriction point,the phosphatase does not activate MPF resulting in arrest of cell cycle at G 2 phase till the repair of damaged DNA is done. This prevents the transfer of defected DNA into daughter cells.

14. Metaphase Checkpoint This occurs at metaphase. Anaphase-promoting complex (APC) regulates this checkpoint. This is also called spindle checkpoint. It checks whether all chromosomes are properly attached to spindle or not. It also governs the alignment of the chromosomes and integrity of the spindles. If there are any mistakes then it delays the cell from entering into anaphase from metaphase.

15. Overview of Cell Cycle Checkpoints

16. Cyclin Dependent Kinases

17. Cyclin Dependent Kinases Inhibitors

18. Cell Cycle Specific Anti- Cancer Drugs