Cell Cycle Regulation PowerPoint PDF

s2c6 Cell Cycle Regulation Dr Paul Dunn Learning Objectives 1 Explain how the cell cycle is regulated by cyclins & Cdks Discuss the changes in cell cycle regulation which lead to 2 uncontrolled growth & cell division in cancer Differentiate between the...

s2c6 Cell Cycle Regulation Dr Paul Dunn Learning Objectives 1 Explain how the cell cycle is regulated by cyclins & Cdks Discuss the changes in cell cycle regulation which lead to 2 uncontrolled growth & cell division in cancer Differentiate between the actions of oncogenes & tumour 3 suppressor genes in cancer development Explain the significance of p53 in the regulation of the cell 4 cycle Revision A quick revision of: The cell cycle & mitosis (s1c3) is advisable prior to this session  The Cell Cycle Figure 18-2 Essential Cell Biology (© Garland Science 2010)  The Cell Cycle is Strictly Regulated  Cells only divide when they receive signals to do so  Signals include: 1. Is more of this type of cell needed? 2. Is this cell fit & healthy & not carrying a lot of mutations that could ultimately cause cancer?  Checks that everything is complete in one phase before moving to next  e.g. chromosome replication complete before entering mitosis  A cell carries out a number of checks to make sure cell division is appropriate & safe  can arrest the cell cycle at several points if not Checkpoints Figure 18-3 Essential Cell Biology (© Garland Science 2010)  Eukaryotic Cells Require Extracellular Signals to Divide, Grow & Survive  Mitogens  stimulate cell division by overcoming cell cycle “brake” that leads to G0  Growth Factors  stimulate growth (increased cell size) by promoting synthesis & inhibiting degradation of macromolecules  Survival Factors  suppress apoptosis (programmed cell death)  Growth Factors Increase protein synthesis Decrease degradation of macromolecules Figure 18-45 Essential Cell Biology (© Garland Science 2010)  Checkpoint: Spindle Assembly  Mitosis must not complete until all the chromosomes are attached to the mitotic spindle  Mitotic checkpoint delays until all chromosomes are attached  Prolonged activation of the checkpoint → cell death  Mechanism of many anti-cancer drugs  Protein Kinases  Most enzyme activity in the cell is also regulated  Even though the enzyme might be present, the cell is able to switch it on or turn it off  One very common mechanism for regulating the activity of a protein is via phosphorylation/dephosphorylation  Adding a phosphate group to an enzyme can induce changes in the 3D structure of the protein → change enzyme activity  Protein kinases are enzymes responsible for adding phosphate groups to other enzymes Cyclins & Cyclin-Dependent Kinases  Proteins called cyclin dependent kinases (CDK) are responsible for regulating the cell cycle  CDKs are inactive unless bound to another protein, a cyclin  When active, CDKs phosphorylate & activate numerous proteins involved in regulating the cell cycle  See Figure Alberts Essential Biology – Fig.18-9 for more specific details Activity of Cyclins Cdk quantity in cell  CDKs are present in the cell throughout the cell cycle  However, on their own they are incapable of regulating the cycle  M-Cyclin concentration increases during interphase & falls during mitosis  Its role is to activate M-Cdk, which then triggers mitosis Alberts 18-5  What Does M-Cdk Do?  M-cyclin + mitotic Cdk = M-Cdk (M-cyclin/Cdk complex)  Phosphorylates & activates key proteins that: 1. Cause chromosomes to condense 2. The nuclear envelope to break down 3. Formation of the mitotic spindle  Other Cyclins  In addition to M-cyclin/Cdk, there are other cyclins/CDKs that regulate the transition to S-phase  S-Cdk activates proteins that: 1. recruit DNA polymerase to replication points on chromosomes 2. triggering DNA replication Relationship Between S-cyclin & M-cyclin Alberts 18-10 CDKs & Cyclins Major Cyclins & Cdks COMPLEX CYCLINS CDKS PARTNER G1-Cdk Cyclin D CDK4, CDK6 G1/S-Cdk Cyclin E CDK2 S-Cdk Cyclin E (early) CDK2 Cyclin A M-Cdk Cyclin A (early) CDK1 Cyclin B Alberts Table 18.2 Cell Cycle Regulation is Complex  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 or preparing for division Cells can remain in G0 for the entire life If a G0 cell does re-enter G1; process can take days  The Cell Can Stop Cycling  The cell will not continue through the cycle if there are problems, or conditions are not ideal Alberts 18-13  CDK & Cancer  Mutations in CDKs & cyclins are common in cancer cells & contribute to cancer promotion  These mutations allow a cell to progress through the cell cycle without the normal checks  Increasing the chance that a cell with potentially cancerous mutations divides  Common mutations seen in skin cancers include:  CDK4 (G1 Cdk)  CDKN2A, CDKN2B (Cdk inhibitors) Advanced Cyclins/CDKs  What Causes Mutations that Lead to Cancer? 1. Spontaneous changes in the genetic code that lead to mistakes (e.g. depurination) 2. Generation of free radicals 3. Changes in DNA caused by components of food (colon cancer) 4. Damage to DNA caused by cigarette smoke (lung cancer, cancer of the throat, tongue, palate) 5. Damage to DNA caused by UV light (skin cancers)  Exposure to UV Light  UV light has the potential to damage DNA  Promotes covalent linkages between two adjacent pyrimidine bases (C or T)  e.g. thymine dimers  May cause mispairing (e.g. C=A) as the strand is copied or stop replication altogether  Unless repaired, pyrimidine dimers can lead to an inhibition of transcription, DNA mutations, cell death & skin cancer Thymine Dimer Formation Alberts, Figure 6-24 Thymine Dimer Formation & repair https://www.thevirtualnotebook.com/dna-repair-definition-mechanism-types/  Oncogenes & Tumour Suppressor Genes  What Gives Rise to a Cancer Cell?  During the initiation phase, mutations occur in normal genes (proto-oncogenes) that normally regulate cell growth & cell division  The mutated gene, now called an oncogene, stimulates the cell to grow & divide more rapidly than usual  During the second phase of cancer, mutations occur in genes that normally stop cells from dividing or induce apoptosis  These genes are called tumour suppressor genes 3 Classes of Cancer Causing Genes Oncogenes Tumour Suppressor Genes Accelerate Brake Mutator Genes Repair, keep the car running smoothly  3 Classes of Cancer Causing Genes 1. Oncogenes  Gain-of-function mutation, activation promotes cancer development  Genes have a positive effect on cell growth & proliferation - i.e. protein kinases, growth factors, mitogens, etc. 2. Tumour Suppressor Genes  Loss-of-function mutations, inactivation promotes cancer development  Genes have a negative effect on cell growth & proliferation - i.e. checkpoint, repressors, pro-apoptotic, etc. 3. Mutator Genes  Indirectly responsible for cancer development; loss-of-function allows mutations to accumulate  Genes normally involved in DNA replication & DNA repair  Proto-Oncogenes & Oncogenes  Proto-oncogenes are normal genes which promote cell division  Protein kinases, growth factors, transcription factors, etc.  Mutant form of proto-oncogene = oncogene  A single mutation creates an oncogene sufficient to promote cell division  Gain-of-function or dominant mutation  Expression at the wrong quantity, time or cell type can leads to uncontrollable cell division & cancer Oncogene Activation  Proto-Oncogene: RAS  Normal RAS flips back & forth between:  Active = bound to GTP  Inactive = bound to GDP  When active RAS stimulates regulators of cell proliferation  30% cancers have a RAS mutation  Amino acid change impairs GTP hydrolysis  RAS remains active, continually stimulating cell division  Also see Figure 16-37  Tumour Suppressor Genes  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 is usually required to allow cell division  Loss-of-function or recessive mutation  Loss of control over cell proliferation, uncontrolled cell growth leading to tumour promotion Tumour Suppressor Gene Inactivation  Tumour Suppressor Gene: p53  First discovered as the causative mutation in Li-Fraumeni syndrome  >50% of human cancers involve an abnormal p53 gene  Referred to as the “Guardian of the Genome”  Expressed when cells exposed to DNA damaging agents  Normal p53 stimulates the expression of p21 p53  p21 stimulates cell cycle arrest  DNA repaired or cells undergo apoptosis  Protects cells from DNA damage, preserving genomic integrity  p53 mechanism of action  Following cellular stress, p53 induces the expression of p21, a Cdk inhibitor  Also known as CDKN1A  Cells arrest in G1 to allow for DNA repair  In the absence of p53 activity, no p21 is synthesized  Cell cycle is NOT halted, cells divide with damaged DNA Figure 18-16 Essential Cell Biology (© Garland Science 2010) Cancer Genes https://www.youtube.com/watch?v=l4Ul9LaYg_w  Oncology Genetics  The majority of cancers are sporadic  Progressive accumulation of acquired genetic mutations &/or epigenetic changes during a person's lifetime  Mutations are somatic, affecting a particular tissue & are not heritable  Some individuals are born with a single gene mutation which can greatly increase susceptibility to one or more types of cancer  Progressive accumulation of other genetic mutations is required, but the inherited mutation makes this more likely to occur  Requires a 2nd hit → Knudson hypothesis  The original mutation can be passed from generation to generation resulting in inherited cancer  Accumulation of Mutations Causes Cancer Normal Cell Malignant Cell Genetics and Cell Processes for Cancer Hereditary Sporadic E.g. Oncogene mutation E.g. TSG mutation E.g. DNA-repair gene mutation Nature Reviews Molecular Cell Biology 11, 220-8 Intratumour Heterogeneity Overview of Carcinogenesis Normal MUTAGENS cell INHERITED Chemicals Radiation, UV Successful MUTATIONS repair Apoptosis Viruses DNA repair DNA Damage Cell growth Failed repair Mutations in somatic cells Activation of growth- Inactivation of tumour promoting oncogenes Impaired apoptosis suppressor genes Altered gene products (proteins); abnormal structural & regulatory proteins Malignant tumour  Resources & Animations  The Cell Cycle – Video Game Simulation  https://www.youtube.com/watch?v=SZk9GrLv8GA  Cell Cycle Checkpoints & Regulation  https://www.youtube.com/watch?v=VLJF8Pf8spw  Cell Division & Cancer  http://www.youtube.com/watch?v=SnaCvuUZoqM  Oncogenes & Tumour Suppressor Genes  https://www.youtube.com/watch?v=l4Ul9LaYg_w  Osmosis:  Oncogenes and tumor suppressor genes: Video & Anatomy | Osmosis  Texts:  Essential Cell Biology 4e, Alberts, Chapter 18 (609-623); Chapter 20 (717-728)  ANY FINAL QUESTIONS?