Podcast
Questions and Answers
What primarily occurs during the G1 phase of the cell cycle?
What primarily occurs during the G1 phase of the cell cycle?
Which phase of the cell cycle is characterized by a cell being terminally differentiated and not re-entering the cycle?
Which phase of the cell cycle is characterized by a cell being terminally differentiated and not re-entering the cycle?
During which phase does the cell check for proper DNA replication before proceeding to the next stage?
During which phase does the cell check for proper DNA replication before proceeding to the next stage?
What is the primary role of the G2 phase in the cell cycle?
What is the primary role of the G2 phase in the cell cycle?
Signup and view all the answers
What key event occurs during prophase in mitosis?
What key event occurs during prophase in mitosis?
Signup and view all the answers
Which checkpoint in the cell cycle checks if mitosis is complete before cell division occurs?
Which checkpoint in the cell cycle checks if mitosis is complete before cell division occurs?
Signup and view all the answers
What role do mitogens or growth factors play in relation to G0 phase cells?
What role do mitogens or growth factors play in relation to G0 phase cells?
Signup and view all the answers
What happens if DNA damage is detected during the G2 phase?
What happens if DNA damage is detected during the G2 phase?
Signup and view all the answers
What is the main activity occurring during metaphase?
What is the main activity occurring during metaphase?
Signup and view all the answers
What triggers the cell cycle checkpoint mechanisms?
What triggers the cell cycle checkpoint mechanisms?
Signup and view all the answers
What occurs at the DNA synthesis checkpoint?
What occurs at the DNA synthesis checkpoint?
Signup and view all the answers
What happens if damage to the cell is beyond repair?
What happens if damage to the cell is beyond repair?
Signup and view all the answers
Which statement best describes the bistable switch mentioned in the cell cycle?
Which statement best describes the bistable switch mentioned in the cell cycle?
Signup and view all the answers
What role do CDKs and cyclins play in the cell cycle?
What role do CDKs and cyclins play in the cell cycle?
Signup and view all the answers
During which phase does cytokinesis occur?
During which phase does cytokinesis occur?
Signup and view all the answers
What is the role of sensors in the cell cycle checkpoints?
What is the role of sensors in the cell cycle checkpoints?
Signup and view all the answers
What is the role of ubiquitination in proteolytic degradation?
What is the role of ubiquitination in proteolytic degradation?
Signup and view all the answers
Which of the following is a commonly mutated cyclin or CDK in cancer?
Which of the following is a commonly mutated cyclin or CDK in cancer?
Signup and view all the answers
How do next-generation CKI inhibitors differ from first-generation inhibitors?
How do next-generation CKI inhibitors differ from first-generation inhibitors?
Signup and view all the answers
What effect does Flavopiridol have on the cell cycle?
What effect does Flavopiridol have on the cell cycle?
Signup and view all the answers
Which tumor suppressor gene is involved in regulating the activity of the E2F transcription factor?
Which tumor suppressor gene is involved in regulating the activity of the E2F transcription factor?
Signup and view all the answers
Which drugs are classified as G1 phase hormonal agents?
Which drugs are classified as G1 phase hormonal agents?
Signup and view all the answers
What is the function of Ispinesib in cancer treatment?
What is the function of Ispinesib in cancer treatment?
Signup and view all the answers
What is the role of cFLIP in apoptosis pathways?
What is the role of cFLIP in apoptosis pathways?
Signup and view all the answers
Which step is crucial for the convergence of apoptotic pathways at the caspase level?
Which step is crucial for the convergence of apoptotic pathways at the caspase level?
Signup and view all the answers
What initiates mitochondrial outer membrane permeabilization (MOMP)?
What initiates mitochondrial outer membrane permeabilization (MOMP)?
Signup and view all the answers
What is the function of SMAC/DIABLO in apoptosis?
What is the function of SMAC/DIABLO in apoptosis?
Signup and view all the answers
How are procaspases activated during apoptosis?
How are procaspases activated during apoptosis?
Signup and view all the answers
Which are characteristics of BCL2 proteins?
Which are characteristics of BCL2 proteins?
Signup and view all the answers
What happens after caspase-8 cleaves BID?
What happens after caspase-8 cleaves BID?
Signup and view all the answers
Which of the following describes IAPs in the context of apoptosis?
Which of the following describes IAPs in the context of apoptosis?
Signup and view all the answers
Which mutations are associated with defects in the extrinsic apoptosis pathway?
Which mutations are associated with defects in the extrinsic apoptosis pathway?
Signup and view all the answers
What is the main role of activated GSDM proteins in pyroptosis?
What is the main role of activated GSDM proteins in pyroptosis?
Signup and view all the answers
Which process is characterized by being regulated and requiring RIPK3?
Which process is characterized by being regulated and requiring RIPK3?
Signup and view all the answers
Which statement best describes necrosis compared to other forms of cell death?
Which statement best describes necrosis compared to other forms of cell death?
Signup and view all the answers
How does autophagy benefit cancer cells?
How does autophagy benefit cancer cells?
Signup and view all the answers
What is a key feature of mitotic catastrophe in cancer?
What is a key feature of mitotic catastrophe in cancer?
Signup and view all the answers
Which of the following drugs activates apoptosis through intrinsic pathway stimuli?
Which of the following drugs activates apoptosis through intrinsic pathway stimuli?
Signup and view all the answers
Which of the following is not a step in the autophagy process?
Which of the following is not a step in the autophagy process?
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.
Related Documents
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.
