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Cell Cycle
| Question | Answer |
|---|---|
| What is the cell cycle? | Orderly sequence of events by which a cell duplicates its contents and divides in two - series of events that take place in a cell leading to its division and duplication |
| What is the cell cycle divided into? | Phases or stages |
| What drives the cell cycle? | Specific molecules signals present in cytoplasm |
| What are the phases of the cell cycle? | Mitotic phase and interphase |
| What is the mitotic phase? | Division of the nucleus |
| What are the stages of mitosis? | Prophase, prometaphase, metaphase, anaphase, telophase, cytokinesis |
| What is cytokinesis? | Division of the cytoplasm |
| What is interphase? | Cell growth and copying of chromosomes in preparation for cell division |
| How much of the cell cycle takes place in interphase? | 90% |
| What are the subphases of interphase? | G1, S, G2, G0 |
| Why is Go not included in the cell cycle? | Because it is in resting phase, postmiotic quiscent - state of withdrawal from cell cycle - neither dividing nor preparing to divide. Instead, cell is "doing its job" performing its fxn within tissue |
| What type of cells are consider Go? | Differentiated cells - muscle, heart, brain, hepatocytes, neurons, fibroblasts |
| Why don't we grow new neurons? | Because its fxn makes it impossible to replicate - have specific place in nervous system. Job is to take a signal from one specific place to another and adding new nerve cells would mess up the specific connections in a complex system |
| What phase is the time between mitosis (or Go) and the synthesis of DNA? | G1 phase |
| What is G1? | First gap, preparatory phase for cell to enter S phase |
| Is G1 phase metabolically active? | Yes, it needs nutrients and growth factors |
| What kind of synthesis occurs during G1 phase? | RNA, protein, lipid, and carbohydrate synthesis |
| Is DNA being replicated during G1 phase? | No, but organelle duplication is |
| How long does the G1 phase last? | 6-24 hours |
| When would the G1 phase be shorter than normal? | In embryonic cells and cancer |
| Is G1 phase always present? | No, in rapidly dividing cells, it can sometimes be non-existent or rapid |
| How does G1 phase prepare for DNA replication? | Checks for cell size, nutrients, growth factors, and DNA damage |
| What is occurring during S phase? | DNA and chromosomal protein synthesis |
| What are examples of chromosomal proteins that are being synthesized during S phase? | Histones |
| How long does the S phase last for? | 7-8 hours in a typical mammalian cell within a 16 hour cycle |
| At what phase is the cell now committed to cell division? | S phase |
| Are growth factors needed during S phase? | No |
| What is the end result of DNA replication? | Two identical daughter genomes |
| What is the G2 phase occuring? | Interval between DNA synthesis (S phase) and mitosis (M phase) |
| What is occurring during G2 phase? | Enzyme, protein, and ATP synthesis - cell growth continues |
| How long does G2 phase last for? | 3 hours within 16 hour cycle |
| What does G2 phase check for? | Cell size and DNA damage |
| How is the cell cycle controlled? | Timer (or clock) - checkpoints and regulators; on/off switch - regulatory proteins |
| Explain the clock or timer control feature in the cell cycle | Provides a fixed amount of time for the completion of each event and a mechanism for initiating events in correct order and only triggered once per cycle |
| Explain the on/off switch feature in the cell cycle | Trigger events in an irreversible fashion |
| What controls the frequency of cell division? | Type of cells and the conditions within the cell/tissue |
| What is the implication of the differences in cell types and conditions for cell cycle regulation? | The differences result from a molecular level |
| A network of regulatory proteins govern the progress through cell cycle, how are these proteins influenced? | Intracellular and extracellular factors |
| Does the cell cycle proceed through a continuous fashion? | No, there are specific checkpoints where cell cycle is stopped until go-ahead signal is received |
| What are the major check points? | G1-S, GS-M, M-G1 |
| What is the most important checkpoint? | G1-S for many cells - rate limiting step, critical control point |
| Is there a Go-G1 checkpoint? | No |
| Is there an S-G2 checkpoint? | No |
| What is the rapidly dividing checkpoint? | M-G1 |
| What are safeguards in cell division? | Correct and complete replication, favorable environmental conditions |
| What are examples of environmental conditions that are checked for? | Enough nutrients, signals from other cells, enough blood supply, enough growth factors |
| Why would the cell cycle need a signal from other cells? | Cell responds to changes in surroundings so when it senses that it is completely surrounded by all sides then it will stop dividing (e.g. a wound) |
| What are checkpoints regulated by? | Factors within cell - health or state of preparation of cell, factors from outside of cell - messages from same tissue or distant cells |
| What is the rate limiting step for replication? | G1-S - critical control point |
| What happens if the cell receives the go-ahead signal at the G1 checkpoint? | Continues on in cell cycle |
| What happens if the cell doesn't receive the go-ahead signal at the G1 checkpoint? | Cell exits cell cycle and goes into non-dividing state (G0) |
| What would prevent entry into M phase? | DNA replication isn't complete, chromosomes aren't properly attached to mitotic spindle |
| What would prevent entry through G1 or G2 phase? | DNA damage - either by radiation, chemicals, or errors |
| What does DNA damage checkpoints allow for? | Time for damaged DNA to be repaired |
| What does G1 check for? | Cell size, nutrients, growth factors, and DNA damage |
| What does G2 check for? | Cell size and DNA damage |
| What does M check for? | Chromosome attachment to spindle |
| What role do cyclically activated protein kinases (CAKs) play? | Cell cycle control system is based on those kinases |
| What affects the levels of CAKs? | Cyclically fluctuating levels of regulator proteins - cyclins |
| What are the two regulatory proteins in a cell cycle? | Cyclins and cyclin-dependent kinases (CDKs) |
| What is the concentration of cyclins during the cell cycle? | Rises and falls depending on the phase of the cell |
| What is the role of cyclins? | Activates CDKs and help control progression from one stage of the cell cycle to the next |
| Why are CDK's called cyclin-dependent kinases? | Activation depends on binding of cyclin. |
| If CDKs depend on the binding of cyclin, what is the concentration of CDKs in the cell cycle? | Are expressed constitutively during cell cycle |
| What is the role of CDKs? | Trigger different steps in the cell division cycle by phosphorylating specific target proteins |
| What are the 4 classes of cyclins? | G1/S cyclins -G1 cyclins, S cyclins, S/G2 cyclins, M cyclins |
| Describe the role of G1/S cyclins - G1 cyclins | G1/S cyclins bind CDKs at the end of G1 and commit cell to replicate. G1 cyclins help promote passage through restriction point in late G1 |
| Describe the role of S cyclins | Bind CDK during S phase, required for initiating replication |
| Describe the role of M cyclins | Promote events of mitosis |
| What other proteins are involved besides cyclins? | CDK activating kinases (CAKs) and CDK inhibitor proteins (CKI) |
| What cyclin is expressed during G1 phase? | Cyclin D - CDK 4 |
| What cyclin is expressed during during G1/S and S phase? | Cyclin E - CDK 2 |
| What cyclin is expressed during S-G2 transition? | Cyclin A- CDK 2 |
| What cyclin is expressed beyond M prophase? | Cyclin B-CDK1 |
| What activates cyclin D - CDK 4? | Growth factors |
| What does cyclin E - CDK 2 do? | Activates proteins for DNA synthesis |
| What does cyclin A - CDK 2? | Regulates mitotic prophase? |
| What does Cyclin B - CDK 1 do | Breakdown of nuclear envelope |
| What are the ways to regulate cyclin-CDK complexes? | Binding of special proteins, (de)phosphorylation of the CDK subunit, proteolysis of cyclins |
| How does binding of special proteins regulate the cyclin-CDK complexes? | CAK - proteins that phosphorylate CDKs in cyclin-CDK complexes and activate them. CKI - proteins that bind to and inhibit cyclin-CDK complexes |
| How does the proteolysis of cyclins regulate cyclin-CDK complexes? | Cyclins are degraded through ubiquitin-proteasome pathway |
| What are tumor suppressor genes? | Retinoblastoma (Rb) and p53 - genes that recognize damaged DNA, among other things |
| If Rb and p53 recognize damaged DNA, what is their role in the cell cycle? | Cell cycle regulators |
| How does Rb function? | Binds and inhibits transcription factors of the E2F family |
| How is Rb activated and inactivated? | Activated when HYPOphosphorylated and inactive when phosphorylated |
| What are E2Fs? | Family of transcription factors that controls proteins that regulate cell cycle |
| What tumor suppressor gene acts as an on/off switch for the cell cycle? | Rb |
| How does Rb act as an on/off switch for the cell cycle? | It is a "brake" at the G1 checkpoint |
| How does Rb binding to transcription factors in the E2F family halt the cell cycle? | When HYPOphosphorylated, binding prevents E2F from transcribing DNA |
| What happens when Rb doesn't bind to E2F? | When phosphorylated, binding does not occur, allowing E2F to do its job and allow transcription to proceed |
| What is the key substrate for Rb? | CDK 4-cyclin D complex |
| Explain how CDK4-cyclin D is a key substrate for Rb | Growth factors and CDK 4-cyclin D phosphorylates Rb which prevents it binding to E2F |
| Growth factors are needed to proceed through cell cycle, what pathway does it travel along? | Ras-MAPK pathway |
| Active E2F allows for what? | Cyclin E and genes for S phase to be translated |
| What are inhibitors of the CDK4-cyclin D complex? | P21, P16/INK4 |
| What are inhibitors of the CDK2-cyclin E | p27 |
| What is the role of p53? | Regulates cell cycle and apoptosis |
| How does p53 regulate cell cycle and apoptosis? | Recognizes and binds damaged DNA |
| What happens after p53 recognizes damaged DNA? | It activates cell cycle inhibitor p21 which then inhibits G2 CDKs thereby inducing cell cycle arrest in response to DNA damage |
| When would there be low levels of p53? | Unstressed DNA |
| How do unstressed cells exhibit low levels of p53? | Continuously degraded or regulatory Mdm2 binds to p53 to block action |
| How does DNA damage arrest the cycle in G2? | DNA damage leads to protein kinases phosphorylating p53 to activate it which accumulates to high levels and stimulates transcription of p21 which then inactivates CDK-cyclin complexes arresting cell in G1 |
| How does p53 accumulate to high enough levels to activate transcription of p21? | Mdm2 normally binds to p53 to block its action but phosphorylation of p53 blocks the binding of Mdm2, allowing it to accumulate to high enough levels |
| What are some other cases where DNA damage would cause an increase in p53, aside from phosphorylating p53? | Phosphorylation of Mdm2 or decrease in Mdm2 production which causes an increase in p53 |
| What is the role of growth factors during the cell cycle? | Acts as signaling molecules to stimulate cellular growth, proliferation, differentiation, and maturation - turns on early response genes and delayed response genes |
| What is the effect of growth factors acting as signaling molecules? | Cytokines, hormones that bind to specific receptors that stimulate/inhibit immune system or cell signaling through various pathways |
| How do growth factors stimulate cell growth, proliferation, differentiation, and maturation? | As a protein/steroid hormone that increases expression of genes that code (e.g. cyclin D and E) |
| What are early response genes? | Usually code for transcription factors to induce many gene products (e.g. cyclins) |
| Why are early response genes called that? | Rapidly activated |
| Can early response gene lead to delayed response gene expression? | Yes |
| What is the implication of being a rapidly activated response gene? | Early response genes are unstable and consequently, fall in concentration as the level of their mRNA which causes a drop in rate of synthesis. It isn't blocked by inhibitors of protein synthesis |
| How are early response genes activated? | Required transcription factors are present in G- cells and are activated by post-translational modifications such as phoshphorylation |
| What are delayed response genes? | Genes induced by activities of transcription factors and proteins produced or activated during early response phase |
| What are examples of early response genes? | c-fos, c-Jun, c-myc proto-oncogenes |
| What are the products of delayed response genes? | CDKs, cyclins, and other components required for cell division |
| What is an example of an external control on progression through cell cycle? | Contact inhibition - inhibition of cell cycle progression due to contact with other cells or basement membrane or other matrix component |
| What is density dependent inhibition? | Contact inhibition with other cells |
| What is anchorage dependence? | Contact inhibition with a basement membrane or other matrix components |
| Do animals cells display anchorage dependence? | Yes, most animal cells must be attached to a substratum in order to divide |
| What is the significance of cancer cells, in respect to the cell cycle? | Don't respond normally to body's control mechanisms (internal or external controls) and forms tumors, masses of abnormal cells within otherwise normal tissue |
| What is PI3K-Akt-mTORC? | Ubiquitous signaling pathway that is often involved in malignancy and the cell cycle, cellular survival, many aspects of insulin and other GF signaling (plus anabolic cellular activity), inflammation/activation of leukocytes |
| How is the PI3K-Akt-mTORC pathway activated? | Extra phosphate groups are added to membrane phospholipids - when inactive kinases associate with these phosphate-rich phospholipids, they become activated |
| What is PI3K? | Kinase that attaches 3 phosphate groups to membrane phospholipids (mostly PIP2) |
| How is PI3K activated? | When a ligand (usually a GF) bind to a receptor |
| What is Akt? | PK B - protein kinase that's activated by binding to the altered phospholipid |
| What also helps activate Akt? | PDK1 also binds to same 3 phosphate phospholipids and helps activate Akt |
| What is the implication of activating Akt? | It activates a wide variety of other regulatory proteins, including MTORC1 |
| What is mTORC1? | Another protein kinase that is very important for cell growth |
| How is mTORC2 different than mTORC1? | It contribute to activation of Akt |
| What role does PI3K play? | Inhibitor of apoptosis |
| How does PI3K inhibit apoptosis? | Once activated, PIP2 becomes PIP3 which serves as docking site for Akt and PDK1 bringing them to PM. MTOR2 phosphorylates Akt, changing its conformation allowing it to be phosphorylated by PDK1. Activated Akt phosphorylates BAD |
| What is the significance of BAD? | Holds apoptosis inhibitory proteins - when phosphorylated, it releases those proteins |
| Are Akt and PDK1 kinases? | Yes, both are kinases |
| How are CDK-cyclin complexes affected by the activation of Akt? | Activated/increases Cyclin A-CDK1, Cyclin D-CDK 4/6 |
| How are inhibitor proteins affected by the activation of Akt? | P21 and P27 (CKIs) are decreased/inactivated - likely due to p53 inactivation |
| What is the net effect of PI3 and Akt activation? | Progression through cell cycle |
| What is Akt also linked to? | Cell survival and many metabolic processes |
| What usually inhibits mTORC1? | Tsc2 usually inhibits mTORC1 unless GF is detected |
| What happens once GF is detected | GF activates PI3K → Akt activation →inactivation of Tsc2 (the mTORC1 inhibitor is inhibited) →activation of mTORC1 →stimulation of a wide range of cell growth processes |
| What does the activation of mTORC1 lead to? | Ribosome, protein, lipid, and nucleotide synthesis; inhibition of protein degradation |
| How is PI3K pathway turned off? | PTEN removes phosphates from PIP3 membrane phospholipids which leads to inactivation of the kinases |
| How much defects in this pathway be linked to carcinogenesis? | Would continue cell growth and division, despite damaged DNA |
Created by:
nnguyen44