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Molecular & Cellular Mechanisms > Cell Cycle, Apoptosis and Cancer > Flashcards

Cell Cycle, Apoptosis and Cancer Flashcards

1
Q

What is cell cycle?

A

Process of cell growth, chromosome replication and division

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2
Q

What is the product of cell cycle?

A

2 daughter cells with the same genetic information

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3
Q

What if cell cycle becomes aberrant?

A

Unchecked cell growth/cancer

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4
Q

What are the stages of interphase, cell growth?

A

G1, S and G2

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5
Q

G1 phase (Gap 1)

A

RNA and protein synthesis due to mitogens and exogenous GFs. Proteins needed to replicate DNA in next phase.

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6
Q

S phase (synthesis)

A

DNA is replicated

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7
Q

G2 phase (Gap 2)

A

RNA and protein synthesis, integrity of DNA checked before mitosis

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8
Q

Mitosis

A
  1. Cell division, nuclear and cytoplasmic
  2. Creates 2 identical daughter cells
  3. Prophase, metaphase, anaphase, telophase and cytokinesis (PMAT)
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9
Q

Go phase (resting)

A
  1. Go cells have exited the cell cycle and are not growing or dividing
  2. They make just enough RNA + proteins for general housekeeping or specialized functions
  3. May re-enter cell cycle at G1 after stimulation by GFs
  4. Terminally differentiated cells can reenter by suppression of CKI, overproduction of cyclin D1, viral oncogenes
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10
Q

Restriction Point

A
  1. GFs are limiting –> cell cycle arrested in G1 at about 2h before starting S phase (restriction point R)
  2. When cells pass R pt, they are GF-independent and complete cell cycle
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11
Q

Checkpoints of Cell Cycle

A

G1, G2 and Metaphase

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12
Q

G1 Checkpoint

A

Verifies integrity of DNA, any DNA damage induces molecular mechanisms to arrest cycle at this point (mitogen deprivation)

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13
Q

G2 Checkpoint

A

Verifies completeness of genomic DNA replication before mitosis

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14
Q

Metaphase Checkpoint

A

Monitors attachment of chromosomes to the mitotic spindle before anaphase and chromosome segregation

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15
Q

DNA Content

A
  1. Resting cells in G1 have DNA content of 2N
  2. In S phase are between 2N and 4N
  3. 4N in G2
  4. 2N after cytokinesis
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16
Q

Labeling cells w/ DNA binding fluorescent dye

A

Able to sort them with FACS cells and different phases can be distinguished

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17
Q

3 cell types in the human body

A
  1. Permanent: remain in Go phase, can’t be regenerated (cardiac, neurons, RBCs)
  2. Stable/quiescent: ability to exit Go and enter G1 with GFs, regenerate damaged tissue (hepatocytes, kidney epithelial cells)
  3. Labile: Never enter Go, constantly dividing to replace lost cell population (gut, epithelium, skin, hair follicles)
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18
Q

Cyclin vs. Cyclin Dependent Kinases

A

Cyclin: Regulatory subunit
CDK: Catalytic subunit

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19
Q

Cyclin, CDK mechanism

A

Cyclin –> CDK –> partial activation of kinase activity –> direct complex to be phosphorylated by proteins

Full activation of CDKs require CDK-activating kinase (CAK)

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20
Q

Cyclin factoids

A
  1. There are many cyclins and CDKs in euk cells, each cyclin can bind to more than 1 CDK and vice versa
  2. Levels of CDKs are constant during cell cycle
  3. Levels of individual cyclins vary during the phases
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21
Q

Cyclin-CDK Complex During Cell Cycle

A
  1. Activity of CDKs varies in different phases of the cell cycle due to transient and cyclical availability of cyclins
  2. At start of G1, cyclin D complexes w/ CDK4 and 6, after cells pass through R pt and enter S phase, cyclin D is degraded
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22
Q

Cyclin-CDK Complex Stages During Cell Cycle

A
  1. cyclin E-CDK2 is active in G1–>S transition
  2. cyclin A-CDK2 is active in S phase to induce enzymes for DNA synthesis
  3. cyclin A-CDK1 and cyclin B-CDK1 initiate mitosis
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23
Q

Inhibitors of cyclin-CDK complex

A

WEE1 kinase, CKIs (CIP/KIP and INK4)

INK4 is specific to G1 CDKs
CIP/KIP bind to G1/S CDKs

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24
Q

Retinoblastoma protein

A
  1. RB = substrate of G1 and G1/S Cyclin-CDK complexes
  2. RB = tumor-suppressor protein b/c it can arrest the cell cycle at G1 checkpoint
  3. Hypophosphorylated RB binds to E2F –> Sequesters E2F and prevents from triggering transcription of cyclin E and cyclin A, DNA replication proteins
  4. Hyperphosphorylation of RB by G1, G1/S CDKs release E2Fs –> transcription of cyclin E so cells can transit G1 and enter S phase
  5. S phase and M phase cyclin-CDK complexes keep RB phosphorylated, degradation of these cyclins –> dephosphorylation of RB
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25
Q

p53 tumor suppressor gene

A

Re-write.

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26
Q

Proteolysis of Cyclins

A

Accomplished by polyubiquitination catalyzed by Ub-ligase. Specific Ub-ligase can ub CKIs to degrade them, releasing inhibition of S phase cyclin-CDK complexes

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27
Q

Failure of Checkpoints in Cell Cycle

A
  1. Result in cancers.
  2. DNA Damage Checkpoints (G1, G2)
  3. Spindle Assembly Checkpoint (M)
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28
Q

Activation of Cell Cycle

A
  1. Myc activation (oncogene)
  2. Active G1 CDK
  3. Inhibit Rb (phosphorylate)
  4. Release E2F
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29
Q

Hypo and hyperphosphorylation of RB

A
  1. Hypophosphorylated (active), RB blocks G1/S transition
  2. Hyperphosphorylation (inactive), RB allows G1/S transition
  3. E2F turns on Cyclin E and Cyclin A –> Activate CDK2 and keep RB inactive/E2F active
30
Q

CDK needs 2 steps to be active

A
  1. Association of a cyclin

2. High levels of cyclin

31
Q

Cyclin-CDK Complex

A
  1. Heart of cell-cycle control
  2. Causes changes in phosphorylation of substrates that regulate cell cycle events
  3. Cyclins are proteins that regulate CDKs, withouth it CDK is inactive
32
Q

CDK Inhibitors

A

CKI’s –> CIP/KIP, p27

Inactivates kinase activity of CDK

33
Q

Cyclin-CDK-CAK Mechanism

A
  1. Cyclin binds to CDK and causes T-loop to move out of active site
  2. CAK phosphorylates CDK at active site and activates enzyme
34
Q

Four Major Classes of Cyclins in Vertebrate Cells

A
  1. Cyclin D (G1) – Complex with CDK4 and CDK6
  2. Cyclin E (G1/S) – Complex with CDK2
  3. Cyclin A (S) – Complex with CDK2
  4. Cyclins A/B (M) – Complex with CDK1
35
Q

Regulation of Cyclin-CDK Activity

A
  1. Phosphorylation of CDK
  2. Binding of CKI P21
  3. Proteolysis of cyclins
36
Q

Wee1 / CDC 25 CDK inhibitor/regulator mechanism

A
  1. Wee1 phosphorylates the “roof” site, inhibits CDK activity
  2. CDC25 is a phosphatase taht dephosphorylates “roof” site to increase CDK activity
37
Q

CAK

A

CDK Activating Kinase

38
Q

CKI Mechanism

A
  1. Binds to both CDK and Cyclin to inactivate

2. Used for control of G1/S CDKs and S CDKs

39
Q

Anaphase-promoting complex or cyclosome (APC/C)

A
  1. Used to regulate protein degradation to progress mitosis from metaphse to anaphase
  2. APC/C is a member of ubiquitin ligase family of enzymes
  3. Eliminates cyclin S and M
40
Q

APC/C activated by binding of CDC20

A
  1. Leads to polyubiquitinization of M-cyclin in M-CDK complex
  2. Because cyclins destroyed, most CDKs inactivated and dephosphorylated
41
Q

Condition to move into anaphase

A
  1. Must get rid of S-cyclin and M-cyclin
42
Q

p53 and tumor suppression

A
  1. p53 is a tumor suppression gene
  2. Tumors inactivate p53
  3. Allow further DNA damage to happen, cancer progression
43
Q

DNA damage activates protein kinases

A
  1. Protein kinases phosphorylate and stabilize p53 protein

2. STOP CELL CYCLE

44
Q

p53 activation/inactivation

A
  1. Phosphorylated p53 (active) increases transcription of p21, a CKI
  2. p21 binds and inactivates cyclin-CDK complexes, causing cell cycle arrest
  3. MDM2 keeps p53 inactive
45
Q

Apoptosis Pathways (2)

A
  1. Intrinsic
  2. Extrinsic

Goal is to maintain cell integrity

46
Q

Intrinsic apoptosis defining characteristics

A
  1. Depend on internal stimuli, abnormalities in DNA
  2. Mitochondrial dependent (mito dysfunction)
  3. BAX/BCL-2 are key regulators
47
Q

Extrinsic apoptosis defining characteristics

A
  1. Depend on external stimuli, removal of survival factors, proteins of TNF family
  2. Mitochondrial independent
48
Q

Common to both apoptosis pathways

A

Caspase 3 is activated in both pathways

Activation of caspases is key to apoptosis

49
Q

Precursor to caspase

A

Procaspase, activated by protease cleavage

Form large/small subunit (tetris piece)

50
Q

2 major classes of caspases

A
  1. Initiator caspases: initiate apoptosis, caspase 8/9

2. Executioner caspases: destroy targets, executes apoptosis (caspase 3)

51
Q

Extrinsic apoptosis pathway

A
  1. Extracellular signals bind to CELL SURFACE DEATH RECEPTORS
  2. Death receptors have 3 classic domains
52
Q

Extrinsic apoptosis mechanism

A
  1. Fas ligand binds to Fas Death receptor
  2. Recruits FADD adaptor protein
  3. Activates Caspase 8/10 –> Caspase 3 (executioner)
53
Q

Intrinsic apoptosis mechanism

A
  1. Cytochrome C is released from mito, binds to pro-caspase activating adaptor protein APAF1
  2. Apaf1 forms APOPTOSOME which activates caspase-9
  3. Caspase-9 activates executioner caspase-3
54
Q

BAX (BH123) protein in apoptosis

A
  1. BAX proteins become activated and aggregate in outer mito membrane, induce release of cytochrome C
  2. Apoptosome formed by binding to APAF1
55
Q

BCL-2

A

Anti-apoptotic BCL proteins

  1. Prevent apoptosis by binding to pro-apoptotic proteins BAX/BH123 to prevent aggregation into active form
56
Q

Intrinsic pathway summary

A

BAX induces cytochrome C release –> APAF1 complex –> Apoptosome –> Caspase 9 –> Caspase 3 (executioner caspase) –> Apoptosis

57
Q

Slide 42 REVIEW PLEASE

A

Apoptosis vs. proliferation

58
Q

2 hit hypothesis of cancer

A

Most of the time need 2 “hits” in order to get cancer – hereditary/sporadic

59
Q

Retinoblastoma – RB Protein

A

Major regulator of cell cycle/apoptosis

60
Q

Retinoblastoma facts

A
  1. Rare human cancer (1:20000)
  2. Occurs in childhood
  3. Result of cell cycle defects
61
Q

Hereditary vs. Sporadic Retinoblastoma

A

Hereditary form inherits LOF/deletion of one copy of RB in every cell. Need to lose that copy to form tumor. Get tumor in both eyes.

Sporadic form needs both copies to have mutation. One eye tumor.

Somatic event causes mutations.

62
Q

Proto-oncogene vs. oncogene

A
  1. Proto-oncogene encode proteins that promote cell growth and division
  2. Converted to oncogenes through gain of function mutations
  3. Oncogenes cause cell proliferation, express oncoproteins

Ras/Src are oncogenes

63
Q

Common Oncogenes

A
  1. NEU -> RTK activation w/o ligand –> Breast cancer
  2. ERBB –> RTK always on –> Glioblastoma
  3. BCR/ABL fusion protein –> Chronic myelogenous leukemia
64
Q

Review Slide 49

A

Gain of Function Mutations in Proto-oncogenes

65
Q

Gain of function mutations and Loss of function mutations

A

GOF for Proto-oncogenes and LOF for Tumor supressor genes

66
Q

Loss of APC is associated with cancer

A

Results in overexpression and cell proliferation

67
Q

Loss of tumor-suppressor gene

A

Increase in cell surface signaling receptors associated with cell proliferation

68
Q

Early adenoma

A

Best stage for early detection of cancers

69
Q

Hanahan and Weinberg Hallmarks of Cancer Cells

A
  1. Self-sufficiency in growth signals
  2. Evade growth suppressors
  3. Activate invasion and metastasis
  4. Enable replicative immortality
  5. Inducible angiogenesis
  6. Resist cell death
  7. Deregulate cellular energetics
  8. Avoiding immune destruction
  9. Tumor-promoting inflammation
  10. Genome instability and mutation
70
Q

Viral Oncogenesis

A
  1. Virus integrates proto-oncogene to host
  2. Proto-oncogene converted to oncogene by mutation
  3. Mutation occurs during viral replication (very inaccurate, no DNA repair)
  4. c-Src (normal proto-oncogene) vs. v-Src (oncogenic)

Molecular & Cellular Mechanisms (11 decks)

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