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BMSC 220 > Topic 14: The Cell Cycle > Flashcards

Topic 14: The Cell Cycle Flashcards

1
Q

Cell Cycle

A
  • cycle of growth and division within a cell
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2
Q

Four coordinated processes

A
  1. cell growth
  2. DNA replication
  3. distribution of the duplicated chromosomes to daughter cells
  4. cell division
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3
Q

Phases of Cell Cycle

A
  1. Mitosis (M Phase)

2. Interphase

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4
Q

Mitosis Phase

A
  • nuclear division (karyokinesis)
  • most dramatic stage of cell cycle
  • corresponding to the separation of daughter chromosomes
  • ends with cell division
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5
Q

Cytokinesis

A
  • the actual division of a cell following mitosis

- division of cytosol

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6
Q

Interphase

A
  • period between mitoses when chromosomes are decondensed and distributed throughout the nucleus
  • nucleus appears morphologically uniform
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7
Q

Quiescent

A
  • non-dividing stage (G0)
  • neurons and many other cell types remain in this stage
  • cells remain metabolically active but no longer proliferates
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8
Q

G1 Phase

A
  • “START” phase in yeast cells
  • “restriction site” in animal cells
  • after passing decision point, cell is committed to proceed through cell cycle
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9
Q

Checkpoints

A
  1. G1
  2. S
  3. G2
    - DNA damage checkpoints
  4. M: spindle assembly checkpoint
    - problem = cell arrest
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10
Q

G1 Checkpoint

A
  • ensures damaged DNA is repaired before being replicated in S phase
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11
Q

S Checkpoint

A
  • continues monitoring DNA integrity ensures DNA that is damaged is repaired
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12
Q

G2 Checkpoint

A
  • prevents initiation of mitosis if DNA is not completely replicated or is damaged
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13
Q

M Checkpoint

A
  • inhibits spindle assembly if chromosomes not distributed accurately to daughter cells
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14
Q

Regulators of Cell Cycle Progression

A
  1. Cyclins
  2. Cyclin dependent protein kinases (Cdk’s)
    - responsible for triggering major cell cycle transitions and for progression of the cell cycle through checkpoints
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15
Q

Cyclins

A
  • proteins which regulate the activity of enzymes which regulate the cell cycle
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16
Q

Cdk’s

A
  • phosphorylating enzymes that are regulated by cyclins
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17
Q

3 Key Model Organisms

A
  1. frog oocyte: key reg. factor in cytoplasm
  2. yeast: protein kinase
  3. sea urchins: cyclic protein expression
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18
Q

Frog Oocytes

A
  • maturation triggers entry into meiotic division from G2 arrested oocytes
  • identified Maturation Promoting Factor (MPF)
  • -> pushed cell to be in M phase from G2 phase even when arrested
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19
Q

Yeast

A
  • strains carrying mutations in specific genes were identified that were defective in cell cycle progression
  • encoded cell cycle regulator conserved in all eukaryotes (Cdk1)
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20
Q

Sea Urchin Embryos

A
  • go through a series of rapid cell divisions where distinct proteins that are synthesized and degraded during cell cycle were identified
  • discovered proteins called cyclins (A and B)
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21
Q

Molecular Characterization of MPF

A
  • purified from frog oocytes
  • made up of two subunits
    1. Cdk1 (yeast)
    2. Cyclin B (sea urchins)
  • highly conserved regulator of the cell cycle
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22
Q

Cdk1 Regulation

A
  1. Cdk1: alone, unphosphorylated in interphase
  2. Cyclin B binds to Cdk1 (G2)
  3. Cdk1 is phosphorylated at 3 sites
    i) activating site
    ii and iii) inactivating site (2 sites)
  4. 2 inactivating site are dephosphorylated allowing singly phosphorylated Cdk1/Cyclin B complex to activate other proteins that will carry the cell into mitosis
    - APC/C = protein
  5. activated Cdk1 = degradation of Cyclin B
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23
Q

APC/C

A
  • anaphase-promoting complex/cyclosome
24
Q

G1

A
  • passage through start regulated by Cdk1 in association with G1 Cyclins
  • Cyclin D
25
Q

G2

A
  • entry into mitosis is regulated by Cdk1 in association with G2 cyclins
  • Cyclin B
26
Q

Mechanisms of Cdk Regulation

A
  1. association with cyclins
  2. activating phosphorylation f threonine around position 160
  3. inhibitory phosphorylation of threonine 14 and tyrosine 15
  4. association with Cdk inhibitors (CKI’s)
27
Q

Cdk Inhibitors

A
  • Interact with monomeric Cdk and prevent association with cyclin
  • Inhibit kinase activity of Cdk/cyclin dimer
28
Q

Karyokinesis

A
  • mitosis
  • the chromosomes condense
  • the nuclear envelope of most cells breaks down
  • the cytoskeleton reorganizes to form the mitotic spindle
  • chromosomes move to opposite poles
29
Q

Cytokinesis

A
  • Cell division

- the Golgi apparatus fragments and the cytoplasm divides

30
Q

Targets of Cdk1/Cyclin B

A 
Karyokinesis
1. chromatin condensation
2. nuclear envelope breakdown
Cytokinesis
3. fragmentation of Golgi apparatus
4. spindle formation
31
Q

Cohesins

A
  • proteins that bind to DNA in S phase

- maintain linkage between sister chromatids following DNA replication

32
Q

Condensins

A
  • are activated by ℗’d Cdk1 and replace the cohesins (except those at the centromere)
  • induce chromatin condensation
33
Q

MCC

A
  • mitotic checkpoint complex
  • inactivates APC/C
  • forms at unattached kinetochores
  • dissociates when all chromosomes are aligned on the mitotic spindle
34
Q

APC/C in Anaphase

A

1) degradation of cyclin B

2) degradation of remaining cohesion proteins allowing separation of chromatids

35
Q

Breakdown of the Nuclear Envelope

A
  • driven in part by phosphorylation of nuclear lamins by Cdk1/cyclin B, which causes the lamins to depolymerize
36
Q

Fragmentation of Golgi Apparatus

A
  • fragments into small vesicles at mitosis (may be absorbed into ER or distributed directly to daughter cells at cytokinesis) due to ℗’n of Golgi matrix proteins by Cdk1
37
Q

Spindle Formation

A
  • microtubule associated proteins are phosphorylated by Cdk1 (and other kinases), which results in increased dynamic instability of microtubules
38
Q

Cytokinesis is triggered by..

A

inactivation of Cdk1

39
Q

Cytokinesis Process

A

A contractile ring of actin and myosin II filaments forms beneath the plasma membrane beginning in anaphase but is most active during telophase and mediates cytokinesis

40
Q

Cyclin D

A
  • critical link btw growth factors signalling and cell cycle progression
41
Q

Cyclin D Synthesis

A
  • continues as long as growth factors activating this pathway continue to be present
  • drives cells past restriction point and allows for continued cell division
  • rapidly degraded and cell division stops quickly in the absence of growth factors
42
Q

Tumor Suppressor Gene

A
  • a gene whose inactivation leads to tumor development
43
Q

Rb

A
  • A key substrate of cdk4,6/cyclin D
  • tumor suppressor
  • a transcriptional regulatory protein that controls cell cycle progression, and is encoded by the Rb tumor suppressor gene that was identified by the genetic analysis of retinoblastoma
  • key role in coupling the cell cycle machinery to the expression of genes required for cell cycle progression and DNA synthesis
44
Q

Cell Regulation of Rb an dE2F

A
  • Actived Rb maintains E2F (family of transcription factors) in an inactive form in either G1 or G0
  • Phosphorylation of Rb causes it to dissociate from E2F, allowing E2F to activate transcription of genes involved in cell cycle progression = cell cycle passes restriction point and enters S phase
45
Q

Growth Factors

A
  • presence of growth factors stimulates Cyclin D expression which phosphorylates Rb thereby allowing E2F to activate genes required for progression of cell cycle past the restriction point in G1 and to move into S phase
46
Q

Cell Proliferation

A
  • regulated not only by growth factors but also by a variety of signals that act to inhibit cell cycle progression
47
Q

DNA Damage Checkpoint

A
  • initiated by protein kinases (ATR and ATM)
  • components of protein complexes that recognize damaged or unreplicated DNA
  • These kinases phosphorylate and activate checkpoint kinases (Chk1 and Chk 2) that bring about cell cycle arrest
48
Q

p53

A
  • a target of checkpoint kinases
  • a transcription factor that is stabilized and activated by phosphorylation from both ATM and Chk1
  • -> increase in p53 levels in response to DNA damage
  • -> induces expression of Cdk inhibitor = cell arrest
  • -> arrest allows from repair
49
Q

Loss of p53 Function

A
  • removes block to cell cycle arrest
  • allows damaged DNA to be replicated and cell cycle to complete
  • is a tumor suppressor
50
Q

Regulation of Cell Death

A
  • cell death must be balanced by cell renewal

- cells normally lost in tissues due to sloughing off, necrosis, or through an active process (apoptosis)

51
Q

Apoptosis

A
  • Programmed Cell Death
  • carefully regulated so that the fate of individual cells meets the needs of the organism as a whole
  • removal of damage/nonfunctional cells
  • key role in eliminating unwanted cells
52
Q

Abnormalities in Apoptotic Process

A
  • cancers, autoimmune diseases, neurodegenerative disorders

- some diseases result from accumulation of errors over multiple generations of cell division

53
Q

Characteristics of Apoptotic

A
  • an active, tightly regulated process of programmed cell death
  • characterized by cleavage of chromosomal DNA, chromatin condensation and fragmentation of both the nucleus and cell
54
Q

C.Elegans

A
  • short life cycle
  • transparent
  • identified several mutation in genes that prevented cell death in cells normally programmed to die, or caused cell death in cell that would not normally die
  • ced-3 encodes caspase
55
Q

Caspase

A
  • proteases that are “executioners of apoptosis”
  • initiate many of the degradative processes of apoptosis
  • exist in cell as inactive precursors and are activated by proteolytic cleavage
56
Q

p53 and Apoptosis

A
  • if DNA damage is beyond repair:
  • p53 levels continue to increase
  • p53 induces apoptotic genes PUMA and Noxa
  • initiates a cascade of reactions which activates cascade 9 resulting in apoptosis

BMSC 220 (6 decks)

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