Lecture 13: Cell Cycle Control
Cell Cycle Control
Learning Objectives
Features checked at cell cycle checkpoints: Students will identify the specific features that are monitored at each checkpoint during the cell cycle.
Downstream effects of cell cycle regulator molecules: Students will learn to predict the consequences of both normal and abnormal functioning of these regulatory molecules.
Influence of cues on cell cycle regulators: Students will identify how various cues impact the activity of cell cycle regulator molecules.
Failure of cell cycle regulators leading to cancer: Students will be able to describe how the malfunction of cell cycle regulators contributes to the development of cancer.
Overview of Cancer
The discussion explicitly centers around the topic of cancer, which is a broad category of diseases characterized by uncontrolled cell growth.
Cell Division Rates and Types of Cells
Intestinal Cells:
Go through two cell cycles per day.
Consideration: Which phases of the cell cycle are significantly shortened to achieve this rapid division?
Nerve Cells:
(Almost) never divide.
Consideration: Which phase of the cell cycle do these cells predominantly remain in?
Cell Cycle Checkpoints
Checkpoints: Critical control mechanisms that ensure cells do not proceed through the cell cycle until specific conditions are met.
G1 Checkpoint:
Checks for:
Cell size
Nutrients
Growth factors
DNA damage
S (Synthesis) Phase: DNA replication occurs.
G2 Checkpoint:
Checks for:
DNA damage
Completeness of DNA replication
M (Mitosis) Checkpoint (Spindle Checkpoint):
Checks for:
Proper attachment of chromosomes to the spindle at the metaphase plate.
Conditions Checked by Specific Checkpoints
Microtubule attachment failure to kinetochores: Checked by M checkpoint.
Mutation due to DNA synthesis error: Checked by G2 checkpoint.
Mutation due to environmental stressors: Also checked by G2 checkpoint.
Checkpoint Regulators
Role of Regulator Molecules: Active during checkpoints; they prevent the division of damaged or otherwise compromised cells.
Outcomes if a cell is prevented from passing through a checkpoint:
The cell may:
Enter a resting state (G0)
Repair DNA damage
Undergo apoptosis (programmed cell death).
Consequences of defective regulator molecules: If checkpoint regulators are defective, cells may continue to divide uncontrollably, potentially forming tumors.
Regulator Molecules: Cyclins
Function of Cyclins: Cyclins are essential for prompting cell movement from one phase to the next. Key cyclins include:
G1 Cyclin (Cyclin D)
G1/S Cyclin (Cyclin E)
S Cyclin (Cyclin A)
M Cyclin (Cyclin B)
Regulator Molecules: Cyclins and Cdks
Cyclins operate by binding to Cyclin-dependent kinases (Cdks).
Function of Cdks: When activated, Cdks phosphorylate target proteins, altering their activity levels.
Mechanism of action:
When a cyclin binds to a Cdk, it activates the Cdk and directs it to specific proteins for phosphorylation.
Example of Target Proteins for Cyclin E-Cdk Complex
Cyclin E bound to Cdk: Phosphorylates and activates proteins that are crucial during the S phase of the cell cycle.
Cyclins Activate Cdks
Presence of Cdks: They are perpetually present but remain inactive without association with cyclins.
Phosphorylation of enzymes (e.g., helicase and topoisomerase): When active, these enzymes initiate S phase (DNA replication).
Regulator Molecules: M Phase Promoting Factor (MPF)
Composition: MPF is a complex of Cdk and Cyclin B.
Threshold Requirement: When Cyclin B concentrations are sufficiently high, MPF is formed.
Role of MPF: Catalyzes phosphorylation of proteins necessary for initiating M phase, such as:
Nuclear lamins for breaking down the nuclear envelope.
Microtubules for the assembly of the spindle apparatus.
Regulator Molecules: MAD (Mitotic Arrest Deficit Proteins)
Function at M/Spindle Checkpoint:
Checks for chromosomal attachment to the spindle.
Inhibition of Anaphase-Promoting Complex/Cyclosome (APC/C) while waiting for correct chromosomal attachments.
Consequences of prolonged incorrect attachment: This condition is termed Mitotic Catastrophe; it may initiate apoptotic pathways via Bcl-2 family proteins.
If attachments are correct: MAD's inhibition of APC/C ceases, allowing MPF to activate APC/C, leading to anaphase.
Regulator Molecules: Anaphase-Promoting Complex/Cyclosome (APC/C)
Function: When chromosomes are correctly attached:
APC/C inhibition by MAD is lifted, leading to the destruction of regulatory proteins via ubiquitination.
Ubiquitin tagging: This process signals degradation of target proteins, which ceases their functions.
APC/C, Separase, and Securin Interaction
APC/C and Cyclin B: At the conclusion of mitosis, APC/C ubiquitinates Cyclin B, resulting in:
(a) Destruction of MPF, (b) Activation of MPF.
Separase role: Separase, when bound to Securin, is inactive; APC/C ubiquitinates Securin, leading to:
(a) Destruction of Securin, (c) Activation of Separase.
Role of Activated Separase
Separase cleaves the cohesin complex that joins sister chromatids, facilitating their separation and the completion of mitosis.
Cancer and Cell Division
Characteristics of Cancer Cells: Often exhibit abnormal chromosome numbers and structures, leading to uncontrolled proliferation.
Mutations Leading to Tumor Development:
Examples: Mutations in negative regulators (e.g., P53 and MAD) may result in their inactivity, while positive regulators (e.g., cyclins) may become overactive.
Regulation of Cdks, Cyclins, and APC/C by Cues
Activity of these regulators is responsive to internal and external cues. Examples include:
Hormonal Growth Factors: In normally functioning cells, these factors lead to:
(a) Increased activity of Cdks and cyclins.
DNA Damage: Typically results in:
(b) Decreased activity of Cdks and cyclins.
P53 Tumor Suppressor Gene
Function of p53: Encodes the p53 protein, which detects DNA damage at the G1 checkpoint.
Mechanism of Action:
When active, p53 acts as a transcription factor that induces the synthesis of Cyclin-dependent kinase inhibitor proteins (CKIs).
CKIs inhibit the cyclin/Cdk complexes, effectively pausing the cell cycle and allowing time for DNA repair.
Activates DNA repair mechanisms, such as nucleotide excision repair, during the G2 checkpoint.
P53 and Cellular Outcomes
If Damage Cannot Be Repaired: P53 triggers:
Apoptosis, leading to:
DNA fragmentation.
Organelle fragmentation.
Fragmentation of the cell into smaller pieces that signal for immune clearance.
Comparison of Normal vs Nonfunctional P53
Normal p53: Activates following DNA damage, leading to CKI production that halts cell cycle progression.
Nonfunctional p53: Cannot bind to DNA, leading to continuing cell cycle progression despite DNA damage, risking the transmission of damaged DNA.
Cancer: Out-of-Control Cell Division
Commonality Across Cancers: All cancers arise from cells with multiple failures in cell cycle regulation.
Predicted Characteristics of Cancer Cells:
Negative regulators like the P53 and MAD will typically show:
(a) Inactivity.
Positive regulators such as cyclins will likely present:
(b) Overactivity.
Genes and Oncogenes
Mutations Leading to Oncogenes: Recapitulates how normal genes that encode proteins involved in cell division can mutate into oncogenes.
Ras Oncogene Example:
Healthy cell dynamics state: In absence of growth factors, Ras remains:
(a) Inactive, (c) Does not divide.
Cancer cell dynamics: Following mutation, Ras remains:
(b) Overactive, (d) Divides uncontrollably.
Consequences of Cancer Cell Division
Impact of Cancer Cells: Cells divide in an uncontrolled manner, infiltrating and impairing healthy tissues, consuming vital nutrients and disrupt the function of normal cellular structures.
Diversity of Cancers: There are at least 200 recognized types of cancer, each with distinct characteristics and implications for affected individuals.