Cell Cycle Overview

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

What primarily occurs during the G1 phase of the cell cycle?

Mitosis completion

DNA replication

Cell growth and protein synthesis (correct)

Nuclear membrane breakdown

Which phase of the cell cycle is characterized by a cell being terminally differentiated and not re-entering the cycle?

S phase

G2 phase

G0 phase (correct)

M phase

During which phase does the cell check for proper DNA replication before proceeding to the next stage?

G1 phase

M phase

S phase (correct)

G2 phase

What is the primary role of the G2 phase in the cell cycle?

Protein synthesis for mitosis Signup and view all the answers

What key event occurs during prophase in mitosis?

Chromosome condensation Signup and view all the answers

Which checkpoint in the cell cycle checks if mitosis is complete before cell division occurs?

M phase checkpoint Signup and view all the answers

What role do mitogens or growth factors play in relation to G0 phase cells?

They can reactivate stem and quiescent cells. Signup and view all the answers

What happens if DNA damage is detected during the G2 phase?

The cell cycle is halted to activate DNA repair. Signup and view all the answers

What is the main activity occurring during metaphase?

Alignment of chromosomes on the metaphase plate Signup and view all the answers

What triggers the cell cycle checkpoint mechanisms?

Problems detected within the cell Signup and view all the answers

What occurs at the DNA synthesis checkpoint?

Verification of DNA replication accuracy Signup and view all the answers

What happens if damage to the cell is beyond repair?

A different set of effectors are activated to induce cell death Signup and view all the answers

Which statement best describes the bistable switch mentioned in the cell cycle?

It transitions based on a balance of positive and negative feedback loops Signup and view all the answers

What role do CDKs and cyclins play in the cell cycle?

They regulate progression through the cell cycle Signup and view all the answers

During which phase does cytokinesis occur?

Telophase Signup and view all the answers

What is the role of sensors in the cell cycle checkpoints?

To detect problems within the cell Signup and view all the answers

What is the role of ubiquitination in proteolytic degradation?

It mediates specific proteolytic degradation targeting the proteasome. Signup and view all the answers

Which of the following is a commonly mutated cyclin or CDK in cancer?

CDK4 Signup and view all the answers

How do next-generation CKI inhibitors differ from first-generation inhibitors?

They are selective in their inhibition of specific CDKs. Signup and view all the answers

What effect does Flavopiridol have on the cell cycle?

It induces cell cycle arrest at G1/S and G2/M phases. Signup and view all the answers

Which tumor suppressor gene is involved in regulating the activity of the E2F transcription factor?

RB protein Signup and view all the answers

Which drugs are classified as G1 phase hormonal agents?

Tamoxifen and megestrol acetate Signup and view all the answers

What is the function of Ispinesib in cancer treatment?

Targets kinesin spindle protein to prevent separation. Signup and view all the answers

What is the role of cFLIP in apoptosis pathways?

It inactivates the pathway by binding to DEDs or FADD. Signup and view all the answers

Which step is crucial for the convergence of apoptotic pathways at the caspase level?

Activation of caspase 3. Signup and view all the answers

What initiates mitochondrial outer membrane permeabilization (MOMP)?

BID and DIM activating BAX. Signup and view all the answers

What is the function of SMAC/DIABLO in apoptosis?

To eliminate the inhibition exerted by IAPs. Signup and view all the answers

How are procaspases activated during apoptosis?

Through proteolytic cleavage at aspartate residues. Signup and view all the answers

Which are characteristics of BCL2 proteins?

They can have pro-apoptotic or anti-apoptotic functions. Signup and view all the answers

What happens after caspase-8 cleaves BID?

It initiates mitochondrial outer membrane permeabilization. Signup and view all the answers

Which of the following describes IAPs in the context of apoptosis?

They inhibit active caspases by binding to their active sites. Signup and view all the answers

Which mutations are associated with defects in the extrinsic apoptosis pathway?

FAS pathway mutations and Caspase-8 suppression Signup and view all the answers

What is the main role of activated GSDM proteins in pyroptosis?

Forming pores in the cell membrane Signup and view all the answers

Which process is characterized by being regulated and requiring RIPK3?

Necroptosis Signup and view all the answers

Which statement best describes necrosis compared to other forms of cell death?

It typically results in the death of a significant number of cells. Signup and view all the answers

How does autophagy benefit cancer cells?

It maintains energy homeostasis and nucleotide pools. Signup and view all the answers

What is a key feature of mitotic catastrophe in cancer?

Aberrant mitosis due to gene defects Signup and view all the answers

Which of the following drugs activates apoptosis through intrinsic pathway stimuli?

SAHA Signup and view all the answers

Which of the following is not a step in the autophagy process?

Nuclear fusion Signup and view all the answers

Study Notes

Cell Cycle

Most cells exist in the G0 phase, terminally differentiated, and generally do not re-enter the cycle. Neurons, red blood cells, and muscle cells are examples. Stem and quiescent cells can be reactivated.
G1 phase: cell growth checkpoint - checks if the cell is large enough and has produced the necessary proteins for synthesis. Monitors internal and external cell environments. Cell growth, protein synthesis, and preparation for DNA replication occur here.
S phase: DNA synthesis checkpoint - checks if DNA has been replicated correctly, if so, it proceeds to M phase.
G2 phase: blocks entry into M phase; detects DNA damage and halts the cell cycle to activate repair mechanisms. Environmental and cellular stress can also trigger the checkpoint.
M phase: mitosis checkpoint - checks if mitosis is complete. If so, the cell divides.
- Prophase: chromosome condensation, nuclear membrane breakdown, duplicated centrosomes separate, and mitotic checkpoint proteins assemble at centromeres.
- Metaphase: chromosomes align on the metaphase plate. Microtubules form the mitotic spindle. Microtubule capture of both centromere regions of a chromatid pair silences the checkpoint. When the last pair attaches, the metaphase is complete.
- Anaphase: spindle pulls apart and separates chromatid pairs.
- Telophase: chromosomes accumulate at their respective poles. The nuclear membrane reforms, chromosomes decondense, and cytokinesis occurs.
Cytokinesis: separation into two daughter cells

Cell Cycle Checkpoints

Cell cycle checkpoints are made of biochemical signaling that triggers cell cycle arrest in response to problems with the cell.
They maintain the integrity of the genome.
They have three parts: sensors, signal transducers, and effectors.
- Sensors are proteins that detect a problem and activate the signal transducer.
- Signal transducers amplify and relay the signal, pushing the cell to make a decision about its fate.
- Effector proteins carry out the decision made by the cell, usually to protect the cell.
If the damage is beyond repair, a set of effectors may be activated that induces a different response such as cell death. ### Bistability in the Cell Cycle
The transition from one phase to another occurs as a bistable switch.
Regulated by feedback loops: positive amplifies the system, and negative inhibits the system.
The resting state switch is off; a stimulus breaks the status quo and turns the switch on.
These switches are tightly controlled by cyclin-CDK complexes. ### CDKs and Cyclins
Regulation of CDKs and Cyclins
- Phosphorylation and dephosphorylation by kinases and phosphatases
- Specific proteolytic degradation is mediated by protein ubiquitination and subsequent targeting of the proteasome for degradation.
Association with cyclins
CDKs in Cancer
- Mutations in p53, p21, CDKs, Rb are commonly seen in cancer.
- Missense mutation in CDK4 blocks its inhibition by INK4 CKIs (melanomas)
- Chromosomal translocations causing overexpression of CDK6 (leukemias)
- Amplification of cyclins D & E (breast cancers, skin cancers)
- CKI p16 INK4A deletion (lung, pancreatic, and colon cancers)
CDK Inhibitors
- First-generation CDK inhibitors are non-selective, for example, Flavopiridol inhibits CDK 1,2,4,6,7, & 9.
- Second-generation CKIs are more selective, for example, Seliciclib inhibits CDKs 2, 7, 9. Palbociclib inhibits CDKs 4, 6.

Tumor Suppressor Genes

Rb Protein: Regulates activity of E2F transcription factors, critical for cyclins expression and genes needed in S phase.
p53 Protein:
- Activated by DNA damage and cell stress via BCL2 family members on the mitochondrial membrane.
- Can be pro or anti-apoptotic.
- Permeabilization of the mitochondrial membrane and release of pro-apoptosis factors is required.
Intrinsic Apoptosis Pathway:
- Initiated by stress or DNA damage
- p53 activation
- BAX/BAK activation
- MOMP (Cytochrome C release)
- Caspase-9 activation
- Caspase-3 activation
- Cell death occurs
Extrinsic Apoptosis Pathway:
- Triggered by death factor ligands
- Adaptor proteins (FADD/TRADD) bind receptor death domains, transfer death signal from receptors to caspases, and recruit procaspase-8 via DEDs.
- DISCs (death-inducing signaling complex)
- cFLIP can inactivate the pathway by binding to DEDs or FADD.

Caspases in Apoptosis

Cysteine-rich aspartate proteases
Molecular scissors that cut intracellular proteins at aspartate residues.
Help break down cellular components for disposal
Synthesized in their inactive form - procaspases.
Activated by cleavage at aspartate residues.
Domino effect – a few caspases can rapidly convert all procaspases to their active forms, amplifying the apoptotic signal. ### BCL2 Proteins
Over 25 members that contain at least one BH domain.
BH3-only pro-apoptotic proteins (i.e., BIM) induce the activity of pro-apoptotic molecules and inhibit anti-apoptotic BCL2 proteins.
Pro-apoptotic members are tumor suppressors
Anti-apoptotic genes are oncogenes.

MOMP

Mitochondrial outer membrane permeabilization.
Process of pro-apoptotic BCL2 family member-regulated release of apoptotic mediators from the mitochondrial compartment.
Initiated by BID and BIM activating BAX.
BAX changes conformation, which increases the permeability of the outer mitochondrial membrane.
Pores are formed due to permeability and release apoptotic mediators, such as cytochrome C and caspase-9. ### IAPs & SMAC/DIABLO
IAPs:
- XIAP inhibits caspases 3 & 7 once they have been processed and binds to their active sites.
- XIAP can also inhibit Caspase-9 by changing its conformation to block the active site.
- NF-κB (a transcription factor) potently inhibits apoptosis and induces transcription of IAPs.
SMAC/DIABLO:
- Eliminates inhibition by IAPs.
- Competes with activated caspase 9 to bind XIAP. ### Defects in Tumor Development
Extrinsic pathway defects:
- FAS pathway mutations
- Caspase-8 suppression (deletions, missense mutations, and hypermethylation).
Intrinsic pathway defects:
- p53 mutations
- ATM, CHK2, MDM2 mutations
- Oncogenic activation of BCL2 due to chromosomal translocation.
Apoptosis-Inducing Drugs
- SAHA
- Most chemotherapeutics induce DNA damage (Intrinsic pathway stimuli).
- Some chemotherapeutics induce TNF (Extrinsic pathway stimuli)
- Loss of p53 makes cells resistant to apoptosis.
- Increased expression of anti-apoptotic proteins (BAX) increases drug resistance. ### Necrosis
Cells can sometimes recover before fully committing.
Passive process
“Untidy” or “Messy”
Ends with the death of many cells – like a bomb going off.
Differences Compared to Apoptosis: SUMO proteins are not involved. ### Pyroptosis
Dependent on caspase or granzyme activation of Gasdermin (GSDM).
Can be induced by chemotherapeutic drugs, activated immune cells, and inflammatory signals (cytokines like IL-1β and TNF-α).
Key Mediator Proteins:
- Pore-forming Gasdermin (GSDM) proteins
- GSDMB, GSDMC, GSDME ### Alternative Death Pathways – Necroptosis, Mitotic Catastrophe, Autophagy
Necroptosis:
- Similar to necrosis.
- Active, regulated form of cell death.
- Requires receptor-interacting serine/threonine-protein kinase 3 (RIPK3).
Mitotic Catastrophe:
- Caused by aberrant mitosis.
- Defects in mitosis genes (i.e., BECN1) can cause tumorigenesis.
Autophagy(means “eating oneself”):
- Recycling system of the cell
- Excessive autophagy triggers non-apoptotic cell death. ### Autophagy
Major Steps:
- Initiation: Pre-autophagosomal structure (PAS) formation and the ULK1 complex.
- Nucleation-elongation-maturation: Conversion from a phagophore to an autophagosome membrane.
  - Nucleation: PI3K complex, ATG9A system.
  - Elongation: ATG12-conj. System, LC3-conj. system
- Fusion: Autophagolysosome is created.
- Degradation: Autolysosome formation.
Benefits to Cancer:
- Cancer cells upregulate autophagy and use the breakdown products to sustain nucleotide pools and energy homeostasis, and maintain their own growth and survival.
- Efficient autophagy in early cancer stages promotes tumor survival.
- Inhibited autophagy: apoptosis/tumor regression, necrosis/inflammation.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

This quiz explores the various phases of the cell cycle, including G0, G1, S, G2, and M phases. It highlights key checkpoints and the significance of each phase in cell growth and division, providing insights into processes such as DNA synthesis and repair mechanisms.