The Cell Division Cycle PDF

The Cell Division Cycle Learning Objectives: Understand the importance of an ordered cell cycle, and consequences of defects in it Understand the events that occur in the four stages of the cell cycle Understand how cyclins and the cell cycle kinases control...

The Cell Division Cycle Learning Objectives: Understand the importance of an ordered cell cycle, and consequences of defects in it Understand the events that occur in the four stages of the cell cycle Understand how cyclins and the cell cycle kinases control the cell cycle Understand the concept of a checkpoint, and the places in the cell cycle where they occur Understand the mechanisms used to control each of the checkpoints Today’s topics 1. Overview of the cell cycle: 4 stages 2. Cyclin-dependent kinases 3. Checkpoint mechanisms  The cell division cycle nucleus chromosomes And organelle Figure 18-1 Essential Cell Biology segregatio  The cell cycle is divided into four phases Growth and preparing for M PHASE (Growth and Figure 18-2 Essential Cell Biology preparing for S PHAS  Duration of the cell cycle varies greatly from one cell type to another Some cells exit the cell cycle and never divide again (like nerve cells). These cells are referred to as “post-mitotic”. Other cells temporarily stop dividing by exiting G1 phase and entering “G0” phase. =>Liver cells are usually in G0 but can re-enter G1 and continue the cell cycle to make more liver cells. Table 18-1 Essential Cell Biology  The Cell Division Cycle What are the challenges facing a dividing cell? Must accurately duplicate all its contents, then divide them equally between the two daughter cells. What would happen if a cell tried to divide before its DNA had replicated? It would be catastrophic as one or both daughter cells would lack part of its genetic material. What would happen if a cell duplicated its DNA but then divided before all its other constituents had doubled? Daughter cells would lack some organelles and/or get smaller and smaller. Cells have mechanisms to precisely coordinate cell growth, DNA replication, and segregation before undertaking cell division. ajor mechanisms control progression of the ce How do cells control the order and timing of events in the cell cycle? yclin-dependent kinases (Cdk): activity of Cdks is regulated and changes throughout the cell cy Checkpoints: ckpoints ensure one phase is completed, before the next phase Today’s topics 1. Overview of the cell cycle: 4 stages 2. Cyclin-dependent kinases 3. Checkpoint mechanisms  The ordering of events in the cell cycle is controlled by Cyclin Dependent Kinases (Cdks) ATP ADP Change in activity! Protein Pi phosphorylated (Substrate) Protein  Cyclin-dependent kinases (Cdks) require “cyclin” proteins for their activity M- Concentration varies during the Kinase present cell cycle throughout “M-cyclin” binding to Cdk create the cell cycle but its The “M-Cdk” kinase activity is dependent on cyclins You examined this protein structure in Section 3!  Cdks associate with different cyclins to induce the different events of the cell cycle nt cyclins will direct the Cdk to phosphorylate different target proteins (“sub S-cyclin M-cyclin synthesis synthesis S-phase substrates M-phase substrates -> DNA replication -> Mitosis Figure 18-10 Essential Cell Biology Today’s topics 1. Overview of the cell cycle: 4 stages 2. Cyclin-dependent kinases 3. Checkpoint mechanisms  The order of events in the cell cycle is controlled by ‘checkpoints’ G2/M “Spindle assembly Checkpoint checkpoint” What is a checkpoint? A molecular mechanism that pauses the cell cycle to ensure that one G1/S sufficient nutrients? step is completed Checkpoint DNA not damaged? before the next is Growth signals received? Figure 18-3 Essential Cell Biology started. Three major checkpoints control the cell cycl Three major checkpoints: G1/S G2/M Spindle assembly Checkpoints make sure conditions are met before G2/M Spindle assembly moving on. If a checkpoint is “activated”, that means the cell cycle stops/pauses at that stage of the cell cycle. G1/S Only when a checkpoint is “satisfied”, does the cycle proceed, This happens by removing or Multiple mechanisms for regulation of Cdk activity Each checkpoint involves G2/M Spindle assembly distinct mechanisms for regulation of Cdk activity: Cdk inhibitor proteins (G1/S checkpoint) Phosphorylation (G2/M checkpoint) G1/S Protein degradation (Spindle assembly checkpoint) Today’s topics 1. Overview of the cell cycle: 4 stages 2. Cyclin-dependent kinases 3. Checkpoint mechanisms 1. G1/S checkpoint  The G1/S (aka G1) Checkpoint Cells that temporarily leave the G cell cycle, withdraw into a state G1/S o called Go Checkpoint “Start” Point at which cells decide whether to enter the cell cycle based on environmental signals Growth factors (like epidermal growth factor, “EGF”) signal animal cells to proceed through the G1/S checkpoint and enter S-phase. Influences cell cycle duration Figure 18-3 Essential Cell Biology  During G1, S-Cdk complexes are formed but bound to inhibitor proteins S-Cdk Cdk inhibitor protein atisfy the G1/S checkpoint, cells reduce the levels of p27 and other Cdk inhi Cells only do this if conditions are favorable for continuing the cell cycle!  DNA damage and the G1/S checkpoint: The role of p53 – the ‘guardian of the genome’ p53 is mutated in about 50% of cancers. Loss of p53 function results in more rapid accumulation of mutations as damaged DNA is not repaired. Conversion of a normal cell to a cancer cell involves Figure 18-15 Essential Cell Biology the accumulation of Today’s topics 1. Overview of the cell cycle: 4 stages 2. Cyclin-dependent kinases 3. Checkpoint mechanisms 1. G1/S checkpoint 2. G2/M checkpoint  M-cyclin is accumulating during S and G2, so why is M-Cdk activity triggered abruptly? G2/M checkpoint M- M- (inactive) M-phase substrates Figure 18-10 Essential Cell Biology  The Wee1 kinase enforces the G2/M checkpoint and Cdc25 phosphatase activity satisfies the G2/M checkpoint Cdc25 phosphatase activated Note how we use the words ”active” and Activating phosphatase ”activate” to refer to M- different things in different contexts: M- Activating the Cdk kinase will satisfy the G2/M checkpoint, meaning that Cdc25 and M-Cdk participate in a positive feedback loop Also: Active M-Cdk phosphorylates Wee1 and this inactivates Wee1, so that Wee1 no longer phosphorylates Cdk. Therefore, once M-Cdk levels reach a critical threshold concentration, small amounts of active M-Cdk lead to activation of the entire pool of M-Cdk! What do you think would happen to the cell cycle if you deleted Wee1 kinase? E. The cells would go through M-phase early and then divide early. Yes!! This phosphorylation is a negative regulator of entry into M phase, so if you remove it, cells enter M phase prematurely by ignoring the G2 checkpoint. They divide early, and as cell growth normally continues throughout G2, ‘Wee’ is Scottish for small! the cells get smaller. Today’s topics 1. Overview of the cell cycle: 4 stages 2. Cyclin-dependent kinases 3. Checkpoint mechanisms 1. G1/S checkpoint 2. G2/M checkpoint 3. Spindle-assembly checkpoint (aka checkpoint in mitosis)  The spindle-assembly checkpoint (aka the checkpoint in mitosis) If Cdc25 positive feedback maintains M-Cdk in its active state, how is M-Cdk inactivated by cells? M Cyclin protein levels drop abruptly at the end of mitosis note that satisfying this checkpoint involves loss of M-Cdk activity! Spindle- Spindle- But how? assembly assembly checkpoint checkpoint Figure 18-4 and 18-5 Essential Cell Biology n degradation – Ubiquitin Proteasome System Substrate protein carrying a polyubiquitin chains proteolytic chamber regulatory particle proteasome eins are marked by chains of a small protein called ubiquitin (“ubiquitin egradation The Proteasome binds to ubiquitinated proteins actively unfolds them (uses energy of ATP) transfers the unfolded peptide chain into the proteolytic cham  M-Cdk inactivation at the spindle- assembly checkpoint is triggered by M- cyclin degradation M- M- APC/C is a protein complex that attaches ubiquitin to cyclin. Ubiquitin is a small protein. Several ubiquitin molecules can be covalently linked to proteins as a chain (‘poly- ubiquitylation’). Poly-ubiquitylation of a protein is a common signal in cells that marks the protein for destruction by the ‘proteasome’. We will revisit this checkpoint during the next lecture on mitosis Figure 18-9 Essential Cell Biology  Summary of checkpoint mechanisms Cyclin protein levels: Checkpoints: G1/S G2/M Spindle- assembly G1/S checkpoint S-Cdk inhibitor proteins maintain the checkpoint the checkpoint is satisfied when inhibitor levels are reduced G2/M checkpoint Phosphorylation of M-Cdk keeps it inactive the checkpoint is satisfied when M-Cdk is dephosphorylated Spindle assembly checkpoint M-Cdk remains active at the checkpoint The checkpoint is satisfied when M cyclin is degraded and M-Cdk  Sign the attendance sheet, if PollEV did not work for you