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MCM Exam 2 > Lect 6 Cell Cycle, Apoptosis, and Cancer > Flashcards

Lect 6 Cell Cycle, Apoptosis, and Cancer Flashcards

1
Q

What happens in each of the stages of the cell cycle?

G0, G1, S, G2, and M

A
  • G0 = cells withdraw from cell cycle (environmental conditions or terminal differentiation [neurons, myocytes, RBCs])
  • G1 = RNA/protein synthesis for DNA replication
  • S = DNA synthesis
  • G2 = DNA stability check
  • M = Nuclear division (Mitosis) –> Cell division (Ctyokinesis)
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2
Q

What is the significance of the restriction point?

What phase does it occur?

A

Growth factors are limiting –> Restriction (R) occurs

G1 phase before G1 checkpoint

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3
Q

What is the significance of G1 checkpoint?

A

Occurs in response to DNA damage

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4
Q

What is the significance of G2 checkpoint?

A

Verify complete genomic duplication

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5
Q

What is the significance of the Metaphase checkpoint?

A

Ensures chromosomes attached to mitotic spindle

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6
Q

Retinoblastoma (Rb) Phosphorylation Drives Cells from G1 to S Phase of Cell Cycle

Where is E2F located in quiescent (non-dividing) cells?

How is it released?

What is the importance of E2F?

What is allowed to happen after release of E2F?

A

De-phosphorylated Rb

Cyclin D [CDK4/CDK6] phosphorylates Rb

E2F drives expression of Cyclin E (G1 –> S) and Cyclin A (S phase) that both activate CDK2 (hyper-phosphorylates Rb)

Transition of cells past G1 checkpoint into S phase

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7
Q

Proteins that interact with and regulate CDK’s activity?

Without cyclins, what happens to CDK?

A

Cyclins

They are inactive (no kinase activity)

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8
Q

Regulation of Cyclin CDK Activity

How is it activated?

How is it inhibited?

Significance of CDC25

A
  • Activation:
    • Cyclin bind to CDK –> Partial Activation
    • Full activation needs phosphorylation by CDK-activating kinase (CAK)
  • Inhibition:
    • p27 binds to and inhibits cyclin-CDK complex (inactive) - Regulates early in cell cycle
    • WEE1 phosphorylates roof site of active cyclin-CDK complex (inactive)
  • Dephosphorylates roof site of CDK-cyclin complex (from WEE1) to increase activity
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9
Q

CAK & the T-Loop

What is the T Loop?

What does cyclin binding cause?

CAK does what?

A

Region of CDK blocking active site

T-Loop moves out of active site

CAK phosphorylates T-Loop

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10
Q

Cyclin-CDK Activity Throughout the Cell Cycle

Cyclin-CDKs for G1 Phase?

Cyclin-CDKs for G1/S Transitions?

Cyclin-CDKs for S Phase?

A

Cyclin D-CDK4 & Cyclin D-CDK6

Cyclin E-CDK2

Cyclin A-CDK2

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11
Q

Cyclin Turnover Regulated by Signal-Dependent Protein Degradation

The progression from Metaphase to Anaphase is done with the help of what key regulator?

Member of what type of family of enzymes?

How is it activated?

It polyubiquitinates which cyclins?

A

Anaphase-Promoting Complex (APC/C) (Cyclosome)

Ubiquitin ligase family of enzymes

Binding to CDC20

S- and M-cyclin complexes

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12
Q

p53 and the Cell Cycle

What is p53?

What keeps it inactive?

What triggers its activation?

Activation leads to what?

A

A transcription factor

MDM2 keeps p53 inactive through degradation

DNA damage triggers phosphorylation of p53 and its active form

Increased transcription of CKI (p21)

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13
Q

p21 (CKI) and the Cell Cycle

Transcription of p21 leads to what?

A

Binding to and inactivating cyclin-CDK complexes for G1-S transition (E-CDK2) and S phase (A-CDK2) –> Keeping Rb hypophosphorylated –> Sequesters E2F

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14
Q

Apoptosis: Two Pathways

Differences between Intrinsic & Extrinsic pathways?

What are internal and external stimuli?

A
  • Intrinsic: Mitochondiral Dependent (cytochrome c)
  • Extrinsic: Mitochondiral Independent
  • Internal: DNA abnormalities
  • External: Removal of survival factors; Proteins of tumor necrosis factor family (TNF)
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15
Q

Apaf1 and Intrinsic Pathway

Describe the process

What can inhibit this apoptosis process in the intrinsic pathway?

A
  1. Activated BAX self aggregates (outer membrane) –> Cytochrome C released
  2. Apaf1 activated by cytochrome C –> apoptosome assembly
  3. Procaspase-9 –> Caspase-9 by apoptosome
  4. Caspase-9 activates Procaspases to Caspases-3, -6 and -7 –> Apoptosis
  • BCL-2
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16
Q

Extrinsic Pathway

Describe the process

A

TNF and other “death” receptors –> activation of Procaspase-8 to Caspase-8 –> activation of Procaspases-3, -6, -7 to Caspases-3, -6, and -7 –> apoptosis

17
Q

Proto-Oncogene vs Oncogene

What are proto-oncogenes responsible for?

How are oncogenes formed and what do they do?

What is a common oncogene?

A

Cell growth and cell division

Gain of Function Mutations –> increased expression of protein products and altered proteins not responsive to normal signals

HER2 receptor mutation (Val to Gln) –> receptors to dimerize and Tyr kinase activity activated in absence of ligand –> Breast Cancer

18
Q

Hereditary Form of Retinoblastoma

Why are these cells predisposed to be cancerous?

How does Retinoblastoma occur?

A

Mutation/Deletion of one copy of RB1 (heterozygous)

Somatic mutation occurs eliminating last good copy causing tumors to form (Loss of Heterozygosity)

19
Q

Sporadic Form of Retinoblastoma

How does this non-hereditary condition arise?

A

2 normal Rb genes have 2 independent mutations

20
Q

Tumor Suppressor Functions

Examples

A
  • Repress cell cycle progression; Promote Apoptosis; Couple DNA damage to cell cycle
  • Rb, p53, APC, BRCA1/2
21
Q

Metastasis Suppresors

What are they?

What do they do?

A

Cell Adhesion Proteins

Prevent tumor cells from dispersing; Block loss of contact inhibition

22
Q

6 Hallmarks of Cancer

A
  1. Self Succiency in Growth Signals
  2. Evading Growth Suppressors
  3. Activating Invasion and Metastasis
  4. Enabling Replicative Immortality
  5. Inducible Angiogenesis
  6. Resisting Cell Death
23
Q

Viral Oncogenesis Steps

A
  • Virus infects host
  • Viral genome integrates into host genome, adjacent to proto-oncogene
  • Virus replicates; some containing host’s proto-oncogene
  • Proto-oncogene mutates into oncogene
  • Virus with oncogene infects normal cell –> tumor cell
24
Q

HPV

E6 leads to what?

E7 leads to what?

A

Loss of tumor suppression via p53 degradation

Binds to Rb

25
Q

Chemotherapeutic Agents and Function

Alkylating Agents

Topoisomerase I Inhibitors

Antimetabolites

Cytotoxic Antibiotics

Topoisomerase II Inhibitors

Mitotic Inhibitors

A
  • Block DNA replication
  • Inhibit topoisomerase I (resolves tangles in DNA)
  • Inhibits enzymes involved in DNA synthesis
  • Intercalate between bases in DNA to inhibit DNA synthesis
  • Inhibiti Topoisomerase II (removes supercoils in DNA)
  • Arrest cells in mitosis during metaphase

MCM Exam 2 (14 decks)

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