Cell Cycle. Trends in Cell Biology

Transcription

1 Cell Cycle Trends in Cell Biology

2 Cell Cycle The orderly sequence of events by which a cell duplicates its contents and divides into two Daughter Cells Activities of a cell from one cell division to the next The period between two mitotic divisions

3 Cell Cycle Function To replicate DNA without errors To Segregate the duplicated DNA equally into two daughter cells

4 Cell Cycle G1: Gap 1, Varying time S: DNA synthesis G2: Gap 2 M: Mitosis

5 G1 Phase 1. Longest and most variable phase 2. Many genes involved in cell cycle progression are switched off so that the cell cannot initiate a new round of proliferation. 3. This repressive system is called restriction point. 4. Antiproliferative stimulus or lack of nutrients diverts the cell to terminal differentiation. Hence cells exit the G1 phase of cell cycle and enter G0. 5. If appropriate positive stimuli are received cells overcome the restriction point and trigger gene expression for a new cycle of DNA replication. 6. Faulty restriction points may lead to uncontrolled proliferation under inappropriate conditions hrs out of 24 hrs, 45 percent

6 G 0 phase A cell may pause in the G1 phase before entering the S phase and enter a state of dormancy called the G0 phase, in which the cell really do nothing and remains in resting state, Most mammalian cells do this Cells that are permanently in the G0 phase are called postmitotic cells.

7 S Phase The S phase, is a period in the cell cycle during interphase, between G1 phase and the G2 phase. This event is an essential aspect of the cell cycle Replication of DNA takes place, the amount of DNA in the cell effectively doubles. Most of the Histones production occurs during the S phase. The duration of S phase is relatively constant among cells of the same species

8 G2 phase Similar to G1, G2 is an intermediate phase, a time for the cell to ensure that it is ready to proceed in the cell cycle. This phase occurs between the S phase and m phase G2 can be thought of as a safety gap during which a cell can check to make sure that entire of its DNA and other intracellular components have been properly duplicated.

9 Cell Cycle

10 The Changes in Cell Components

11 Cell cycle in-vivo 1. Cell that are highly specialized. Example???? 2. Cell that normally do not divide but can be induced to begin DNA synthesis and divide when given an appropriate stimulus. Example???? 3. Cells that normally possess a relatively high level of mitotic activity. Example???

12 Cell Cycle Control System The most basic control system should possess the following features: 1. A clock, or timer, that turns on each event at a specific time, thus providing a fixed amount of time for the completion of each event. 2. A mechanism for initiating events in the correct order; entry into mitosis, for example, must always come after DNA replication. 3. A mechanism to ensure that each event is triggered only once per cycle. 4. Binary (on/off) switches that trigger events in a complete, irreversible fashion. It would clearly be disastrous, for example, if events like chromosome condensation or nuclear envelope breakdown were initiated but not completed. 5. Robustness: backup mechanisms to ensure that the cycle can work properly even when parts of the system malfunction. 6. Adaptability, so that the system's behavior can be modified to suit specific cell types or environmental conditions.

13 Cell Cycle Control The processes of DNA replication and mitosis, and intervening events during the cell cycle, occur in a highly ordered and specific manner. A complex network of proteins ensures that these events occur at the proper time. Cyclin-dependent kinase enzymes (CDKs) associate successively with different cyclins to determine cell cycle progression. Regulation of the cell cycle involves steps crucial to the cell, including detecting and repairing genetic damage, and provision of various checks to prevent uncontrolled cell division.

14 Cell-Cycle Checkpoints G1 checkpoint In yeast, called start point In animal cells, called restriction point G2 checkpoint Located at boundary between G2 and M phase Proper completion of DNA synthesis required before cell can initiate mitosis Spindle Assembly Checkpoint Boundary between metaphase and anaphase All chromosomes must be properly attached to these spindle

15 Checkpoints in the cell-cycle control system Information about the completion of cell-cycle events, as well as signals from the environment, can cause the control system to arrest the cycle at specific checkpoints.

16

17 Checkpoints Generally Operate Through Negative Intracellular Signals Negative intracellular signals arrest the cell cycle, rather than through the removal of positive signals that normally stimulate cellcycle progression. Example Mitotic initiation check point (G2 check point) Unreplicated DNA inhibits the initiation of mitosis, creating a stop signal that persists until the completion of DNA replication. Spindle check point Each unattached chromosome sends a negative signal to inhibit progress through the cell cycle., the attachment of the last chromosome will be easily detected for progress.

18 Components of Control system Two key classes of regulatory molecules, cyclins and cyclin dependent kinases (CDKs), control the cell cycle Cyclins Cyclins are a family of proteins involved in the progression of cells through the cell cycle Cyclins regulate cell-cycle progression through interactions with cyclindependent kinases (CDKs) CDKs Cyclin-dependent kinases (CDK) belong to a group of protein CDKs are called "cyclin-dependent" because their activity requires their association with activating subunits called cyclins

19 Two key components of the cell-cycle control system. A complex of cyclin with Cdk acts as a protein kinase to trigger specific cell cycle events. Without cyclin, Cdk is inactive.

20 The structural basis of Cdk activation (A)In the inactive state, without cyclin bound, the active site is blocked by a region of the protein called the T-loop (red). (B) The binding of cyclin causes the T-loop to move out of the active site, resulting in partial activation of the Cdk2. (C) Phosphorylation of Cdk2 (by CAK) at T-loop, improving the ability of the enzyme to bind its protein substrates.

21 Molecular mechanisms that regulate Activities of Cdk's

22 1. Cyclin Binding Cyclin-cdk complex activates change in active site conformation Allowing cdk to phosphorylate its substrate 2. Cdk phosphorylation state Regulated by addition and removal of phosphate groups

23 3. Inhibitors of Cell Cycle Progression A variety of signals act to inhibit cell cycle progression The effects of inhibitory signals are also mediated by regulators of the cell cycle machinery, frequently via the induction of Cdk inhibitors. Suppression of cdk activity 1. Inhibitory phosphorylation (wee1) primarily in M-phase 2. Cdk Inhibitor proteins (CDKIs) primarily in G1 and S phase controls

24 The regulation of Cdk activity by inhibitory phosphorylation

25 CDK Inhibitors Except for regulation of cyclin levels, cells develop another regulatory mechanism of cyclin-cdk complex activity CdkIs. CdkIs bind to cyclin-cdk complexes and inhibit their activity, which is extremely important once cell cycle enters into autonomous program, to ensure the fidelity of genetic materials. Degradation of sic1 (cdk inhibitor in G1) allows cyclin-cdk to initiate DNA replication Removal of p27 leads to cell cycle progression

26 The inhibition of a cyclin-cdk complex by a CKI. The p27 binds to both the cyclin and Cdk in the complex, distorting the active site of the Cdk. Also inserts into the ATP-binding site, further inhibiting the enzyme activity.

27 4. Controlled proteolysis Through ubiquitin-proteosome