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Questions and Answers
What is the primary role of cyclin-dependent kinases (CDKs) in the cell cycle?
What is the primary role of cyclin-dependent kinases (CDKs) in the cell cycle?
Which factor is NOT involved in promoting cell growth?
Which factor is NOT involved in promoting cell growth?
What happens when all chromosomes are not attached to the mitotic spindle during cell division?
What happens when all chromosomes are not attached to the mitotic spindle during cell division?
What causes prolonged activation of the spindle assembly checkpoint?
What causes prolonged activation of the spindle assembly checkpoint?
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Which of the following statements is true about the role of growth factors in the cell cycle?
Which of the following statements is true about the role of growth factors in the cell cycle?
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What is the consequence of an inactive CDK complex?
What is the consequence of an inactive CDK complex?
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In cancer development, what is the function of oncogenes compared to tumour suppressor genes?
In cancer development, what is the function of oncogenes compared to tumour suppressor genes?
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What role does the protein p53 play in the regulation of the cell cycle?
What role does the protein p53 play in the regulation of the cell cycle?
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What is the effect of thymine dimers on DNA replication?
What is the effect of thymine dimers on DNA replication?
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Which statement accurately describes oncogenes?
Which statement accurately describes oncogenes?
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What are mutator genes responsible for in relation to cancer?
What are mutator genes responsible for in relation to cancer?
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What distinguishes tumor suppressor genes from oncogenes?
What distinguishes tumor suppressor genes from oncogenes?
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What is a potential outcome of unrepaired thymine dimers?
What is a potential outcome of unrepaired thymine dimers?
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Which of the following best describes the role of proto-oncogenes?
Which of the following best describes the role of proto-oncogenes?
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In which phase do mutations typically convert proto-oncogenes into oncogenes?
In which phase do mutations typically convert proto-oncogenes into oncogenes?
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The primary function of tumor suppressor genes is to:
The primary function of tumor suppressor genes is to:
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What is a common characteristic of gain-of-function mutations in oncogenes?
What is a common characteristic of gain-of-function mutations in oncogenes?
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Which of the following outcomes is associated with an increase in pyrimidine dimers?
Which of the following outcomes is associated with an increase in pyrimidine dimers?
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Which process is directly impaired by mutations in tumor suppressor genes?
Which process is directly impaired by mutations in tumor suppressor genes?
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What is the primary consequence of the activation of growth-promoting oncogenes?
What is the primary consequence of the activation of growth-promoting oncogenes?
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Which of the following is NOT a factor that causes DNA damage leading to mutations?
Which of the following is NOT a factor that causes DNA damage leading to mutations?
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What is the expected outcome if the repair of DNA damage is successful?
What is the expected outcome if the repair of DNA damage is successful?
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What characterizes the altered gene products resulting from mutations in oncogenes?
What characterizes the altered gene products resulting from mutations in oncogenes?
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What is the primary role of the M-Cdk complex during the cell cycle?
What is the primary role of the M-Cdk complex during the cell cycle?
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Which cyclin is associated with the G1/S phase transition?
Which cyclin is associated with the G1/S phase transition?
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What happens to a cell that enters the G0 phase?
What happens to a cell that enters the G0 phase?
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Which of the following factors could cause mutations leading to cancer?
Which of the following factors could cause mutations leading to cancer?
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How do mutations in CDKs contribute to cancer progression?
How do mutations in CDKs contribute to cancer progression?
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What is the function of S-Cdk in the cell cycle?
What is the function of S-Cdk in the cell cycle?
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What is the function of CDK inhibitors like CDKN2A?
What is the function of CDK inhibitors like CDKN2A?
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In which phase does Cyclin A function as an early partner with CDK1?
In which phase does Cyclin A function as an early partner with CDK1?
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What type of damage does a spontaneous genetic change typically cause?
What type of damage does a spontaneous genetic change typically cause?
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What initiates the breakdown of the nuclear envelope during mitosis?
What initiates the breakdown of the nuclear envelope during mitosis?
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What is the role of RAS in normal cell function?
What is the role of RAS in normal cell function?
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What commonly happens in cancers with a mutation in the RAS gene?
What commonly happens in cancers with a mutation in the RAS gene?
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What kind of mutation is typically necessary in tumor suppressor genes to promote cancer?
What kind of mutation is typically necessary in tumor suppressor genes to promote cancer?
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What is the primary function of the p53 tumor suppressor gene?
What is the primary function of the p53 tumor suppressor gene?
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In the absence of functional p53, what is the consequence for the cell cycle?
In the absence of functional p53, what is the consequence for the cell cycle?
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What does the term 'Knudson hypothesis' refer to in the context of cancer genetics?
What does the term 'Knudson hypothesis' refer to in the context of cancer genetics?
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Which statement is true regarding oncogenes?
Which statement is true regarding oncogenes?
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What type of genetic changes primarily contribute to sporadic cancers?
What type of genetic changes primarily contribute to sporadic cancers?
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What is a common characteristic of tumor suppressor genes?
What is a common characteristic of tumor suppressor genes?
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Which of the following statements about cancers associated with p53 mutations is accurate?
Which of the following statements about cancers associated with p53 mutations is accurate?
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Study Notes
Cell Cycle Regulation
- Cells only divide when receiving signals
- Signals include: if more of a specific cell type is required, if the cell is healthy, and if it doesn't have many mutations
- Checks are performed to ensure the completion of each phase before progressing to the next.
- Examples include chromosome replication completion before mitosis.
- A cell has multiple checkpoints to ensure that cell division is appropriate and safe
- If not, the cell cycle is halted.
Learning Objectives
- Explain how the cell cycle is regulated by cyclins & Cdks
- Discuss changes in cell cycle regulation leading to uncontrolled growth & cell division in cancer.
- Differentiate between oncogenes & tumour suppressor genes in cancer development.
- Explain the significance of p53 in cell cycle regulation.
Cell Cycle & Mitosis Review
- A quick review of the cell cycle & mitosis (s1c3) is advisable before the session.
The Cell Cycle
- Interphase: G₁, S, G₂
- M phase: mitosis (nuclear division), cytokinesis (cytoplasmic division)
- A cyclical process: G₁ (growth), S (synthesis-DNA replication), G₂(growth and preparation for division), M (mitosis).
Checkpoints in the Cell Cycle
- G₁ checkpoint: Checks if the environment is favorable and if the cell is healthy
- G₂ checkpoint: Checks if all DNA has been replicated and if any damage has been repaired.
- Checkpoint in mitosis: Checks that all chromosomes are correctly attached to the mitotic spindle.
- Enter S-phase checkpoint: Checks if the environment is favourable.
- These checkpoints are critical to ensure cell processes proceed accurately; and that DNA replicates correctly.
Eukaryotic Cell Signals
- Mitogens: Stimulate cell division by overcoming the cell cycle "brake" leading from G₀ to G₁.
- Growth factors: Stimulate growth by promoting synthesis and inhibiting degradation of macromolecules (enlarging cell size)
- Survival factors: Suppress apoptosis (programmed cell death).
Growth Factors
- Increase protein synthesis.
- Decrease degradation of macromolecules.
Checkpoint: Spindle Assembly
- Mitosis cannot be completed until all chromosomes are attached to the mitotic spindle.
- Mitotic checkpoint delays until all chromosomes are attached.
- Prolonged activation can lead to cell death.
- A mechanism for some anti-cancer drugs.
Protein Kinases
- Most enzyme activity is regulated in the cell.
- Even if the enzyme is present, the cell can switch it on or off.
- Phosphorylation/dephosphorylation is a major regulating mechanism.
- Adding phosphate groups changes enzyme activity.
- Protein kinases add phosphate groups to other enzymes.
Cyclins & Cyclin-Dependent Kinases (CDKs)
- CDKs are proteins that regulate the cell cycle.
- CDKs are inactive unless bound to a cyclin
- When active, CDKs phosphorylate and activate numerous proteins involved in regulating the cell cycle.
Activity of Cyclins
- CDKs are present throughout the cell cycle
- However, on their own they cannot regulate the cycle.
- M-cyclin concentration increases during interphase and falls during mitosis.
- Its role is to activate M-Cdk, triggering mitosis.
What Does M-Cdk Do?
- M-cyclin + mitotic Cdk = active M-Cdk complex.
- Phosphorylates & activates key proteins causing chromosomes to condense, nuclear envelope to break down, and initiate the formation of the mitotic spindle.
Other Cyclins
- In addition to M-cyclin/Cdk, other cyclins/CDKs regulate the transition to S-phase.
- S-Cdk activates proteins that recruit DNA polymerase to replication points on chromosomes and triggering DNA replication.
Relationship Between S-cyclin & M-cyclin
- S-cyclin and M-cyclin levels fluctuate throughout the cell cycle.
CDKs & Cyclins
- Diagram illustrating the cyclical regulation of CDKs and Cyclins.
Major Cyclins & CDKs
- Table listing the complex, cyclins, and CDKs present in cell types
Cell Cycle Regulation is Complex
- Cyclin levels fluctuate during the cell cycle phases.
- Diagram depicting a graphical representation of cyclin levels throughout cell phases.
Cells Can Withdraw from the Cell Cycle & Dismantle the Regulatory Machinery
- G₀ is a quiescent state.
- Cell cycle machinery is dismantled (Cyclins & CDKs disappear).
- Cells are neither dividing nor preparing for division.
- Cells can remain in G₀ for the whole lifespan.
The Cell Can Stop Cycling
- The cell will not continue if problems or conditions are not ideal (damaged DNA, unfavorable extracellular environment), etc.
- The cell checkpoints halt progression of cell division when necessary.
CDK & Cancer
- Mutations in CDKs and cyclins are common in cancer cells, contributing to cancer progression.
- These defects allow cells to progress through the cell cycle without the necessary checkpoints.
- Increasing the chance that a cell with potentially cancerous mutations divides.
Advanced Cyclins/CDKs
- Diagram illustrating cyclin and CDK activities at different stages of the cycle (G₁, S, G₂, and M).
What Causes Mutations Leading to Cancer?
- Spontaneous changes in the genetic code.
- Generation of free radicals.
- Changes in DNA caused by food components (colon cancer)
- Damage to DNA caused by cigarette smoke (lung, throat, tongue, and palate cancer)
- Damage to DNA caused by UV light (skin cancer)
Exposure to UV Light
- UV light has potential to damage DNA.
- Promotes covalent linkages between pyrimidine bases (e.g., thymine dimers).
- May cause mispairing (e.g. C=A) as the strand is copied, or stop replication altogether.
- Unrepaired pyrimidine dimers lead to inhibition of transcription, DNA mutations, etc. (cell death & skin cancer).
Thymine Dimer Formation
- Diagram describing the formation of a thymine dimer following UV light exposure
Thymine Dimer Formation & Repair
- Diagram illustrating how thymine dimers are normally repaired.
Oncogenes & Tumour Suppressor Genes
- Normal genes that regulate cell growth & cell division.
What Gives Rise to a Cancer Cell?
- Initiation phase mutations occur in normal genes (proto-oncogenes).
- Second phase mutations occur in genes that stop cell division.
- Oncogenes- stimulate rapid growth/division
- Tumour suppressor genes- halt growth/division
3 Classes of Cancer Causing Genes
- Oncogenes: gain-of-function mutations promote cancer development.
- Tumour Suppressor Genes: loss-of-function mutations promote cancer development.
- Mutator genes: indirectly responsible for cancer development due to mutations accumulating that are involved in DNA replication and repair.
Proto-Oncogenes & Oncogenes
- Proto-oncogenes are normal genes promoting cell division (e.g., protein kinases, growth factors, transcription factors)
- Mutant form of proto-oncogene is an oncogene.
- A single gain-of-function mutation creates an oncogene sufficient to promote cell division.
- Incorrect expression can cause uncontrollable cell division.
Oncogene Activation
- Dominant mutation (gain-of-function)
- Single mutation event in proto-oncogene creates oncogene
- Activating mutation allows oncogene to stimulate cell survival and proliferation.
Proto-Oncogene: RAS
- Normal RAS swaps between Active (bound to GTP) and Inactive (bound to GDP) states.
- When active, RAS stimulates regulators of cell proliferation.
- About 30% of cancers have a RAS mutation (amino acid change impairing GTP hydrolysis).
- RAS remains active continuously, stimulating cell division.
Tumour Suppressor Genes
- Normally prevent cells from dividing (cell cycle checkpoints & apoptotic inducers).
- Cancer can be caused by loss of genes that inhibit cell division.
- Mutations of both copies of a tumour suppressor gene usually require to allow cell division.
- Loss-of-function mutations.
- Loss of control of cell proliferation leading to tumour promotion.
Tumour Suppressor Gene Inactivation
- Recessive mutation (loss of function)
- Two inactivating mutations in tumour suppressor genes resulting in loss-of-function and uncontrolled cell proliferation.
Tumour Suppressor Gene: p53
- First discovered as a causative mutation in Li-Fraumeni syndrome.
- About >50% of human cancers involve abnormal p53 gene..
- Referred to as the 'Guardian of the Genome'.
- Expressed when cells are exposed to DNA damaging agents.
- Normal p53 stimulates p21 production
- p21 causes cell cycle arrest for DNA repair; or apoptosis.
p53 Mechanism of Action
- Following cellular stress, p53 induces expression p21.
- p21 is a CDK inhibitor (known as CDKN1A) halting cell division.
- Cells arrest in G₁ to allow DNA repair or undergo apoptosis.
- Without p53, p21 is not synthesized, leading to cells dividing with damaged DNA.
Cancer Genes
- Overview of cancer, cell cycle, and cell division.
Oncology Genetics
- Majority of cancers are sporadic (not heritable).
- Mutations are somatic & affect a particular tissue
- Some individuals are born with a single gene mutation, increasing susceptibility, requiring progressive mutations for occurrence,
- Two-hit model/Knudson hypothesis- (inherited or sporadic cancers require two "hits")
Accumulation of Mutations Causes Cancer
- Diagram showing accumulation of mutations leading to the development of malignant cells.
Genetics and Cell Processes for Cancer
- Diagram summarizing the genetic and cellular processes associated with cancer development.
Intratumour Heterogeneity
- Diagram showing that tumours are comprised of diverse cell variants, reflecting variations in genomic instability.
Overview of Carcinogenesis
- Diagram outlining the stages of carcinogenesis, from initial DNA damage through mutations to the progression of a malignant tumor.
Resources & Animations
- Links to relevant video lectures and other multimedia resources.
Additional Information
- Text: Essential Cell Biology - 4e, Alberts.
- Key chapters: Chapter 18 (609-623) and Chapter 20 (717-728).
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Explain how the cell cycle is regulated by cyclins & Cdks Discuss the changes in cell cycle regulation which lead to uncontrolled growth & cell division in cancer Differentiate between the actions of oncogenes & tumour suppressor genes in cancer development Explain the significance of p53 in the regulation of the cell cycle
