Cell Cycle

Question 1

Phases of Cell Cycle

Answer 1

G1
S (DNA replication here)
G2
M (mitosis and cytokinesis)
G0: if extracellular conditions unfavorable, G1 progress delayed and might enter G0 in which cells are quiescent or senescent.

Question 2

Checkpoints in cell cycle

Answer 2

Ensures that cell cycle proceeds without errors

(1) G1-S
(2) S-G2
(3) G2-M
(4) Restriction point in G1 at which cell commits to going through cell cycle. If don’t get past this, stay in G1 or even go to G0

Question 3

G1 Restriction Point: what happens when this is passed?

Answer 3

(1) Rb protein is phosphorylated by G1-CDK

(2) E2F trx factor released and activates necessary genes for cell to enter S phase

Question 4

Rb mutations are seen in ___

Answer 4

Retinoblastoma

Question 5

Checkpoint signaling

• ATM: activated by, triggers, steps
• ATR: activated by, triggers, steps

Answer 5

• ATM activated by double stranded DNA breaks and triggers G1 checkpoint. ATM activates CHK2 and p53 to stop cell from entering S phase
• ATR activated when single stranded DNA joins with double stranded DNA and triggers intra-S phase and G2 checkpoints. ATR activates CHK1; CHK1 phosphorylates Wee1 (activates) and CDC25 (inhibits) to prevent cell cycle from progressing

Question 6

Cell cycle can be stopped due to:

Answer 6

Unfavorable extracellular environment, DNA damage, unreplicated DNA

Question 7

Cyclin-dependent kinases (CDKs)

• Active form does what wrt cell cycle?
• Need ___ to be active and to be directed to target proteins.
• Regulated by phosphorylation:
  (1) What does activating ppylation?
  (2) Inhibitory ppylation? Gets signals from?
  (3) Activating deppylation? Does what? Important for which transitions?
• Describe how positive feedback works and what it does wrt cell cycle.

Answer 7

• Active form ppylates downstream targets necessary for cell cycle to continue
• Need cyclin to be active and to be directed to target proteins.
  (1) CDK activating kinase (CAKs). CAK activity is high throughout cell cycle.
  (2) Wee1 kinase. Ppylates Cdk1, inhibits transition from G2 to M. Gets signals from DNA damage or if cell is not proper size for mitosis.
  (3) Cdc25 is a phosphatase and counters Wee1. Activates CDKs and is important for G1-S and G2-M transitions.
• CDK can activate itself via positive feedback loop by activating Cdc25 and inactivating Wee1.

Question 8

CDK inhibitors

• Important ones
• Activated by?

Answer 8

• p16, p21, p27

- DNA damage

Question 9

What is SCF?

Answer 9

E3 ligase specific to CDK inhibitors.

Question 10

Cyclin

• Levels?
• Types?
• Degraded by?

Answer 10

• Level fluctuate throughout cell cycle
• Each CDK has unique cyclin that activates it
• Degraded through ubiquitin pathway

Question 11

What are mitogens?

Answer 11

Factors that promote cell proliferation

Question 12

Protein degradation ubiquitin pathway

Answer 12

E1 activates ubiquitin; E1 transfers activated ubiquitin to E2 (ubiquitin conjugating enzyme); E2 forms complex with E3 (substrate specific ubiquitin protein ligase); Ubiquitin transferred to lysine residue itself, as chain, or on various parts of protein; Proteins then degraded by 26S proteosome.

• Ubiquitin is recycled
• 26S proteasome has 19S and 20S parts
• Important because protein degradation controls cell division, signal transduction, gene expression, apoptosis

Question 13

Li-Fraumeni syndrome

Answer 13

Disease that predisposes individuals to cancers due to mutations in p53

Question 14

p53 is?

• How does it work?
• Can also be activated by?

Answer 14

p53 is a trx factor that regulates cell cycle checkpoints, DNA repair, and apoptosis.

• Usually inhibited by Mdm2.
• DNA damage detected –> ATM/ATR pathway ppylates p53 and frees it from Mdm2 –> p53 binds to regulatory region of p21 (CDK inhibitor) and upregulates its trx –> p21 inhibits G1/S and S CDKs
• Can also be activated by oncogenes: overproduction of Myc oncogene protein leads to trx of Arf (alternative reading frame) protein –> Arf removes Mdm2 –> p53 activated

Question 15

Two broad classes of cell growth arrest

Answer 15

(1) Quiescence: growth factor deprivation; reversible

(2) Senescence: cellular aging; irreversible

Question 16

Types of senescence

Answer 16

(1) Oncogene induced
(2) Replicative: triggered by exposed single-stranded telomeric regions which only occurs when telomere is too short to form a T-loop and cells reach Hayflick’s limit. Shelterin helps form T-loop

Question 17

Telomerases

Answer 17

Active in development and in cancerous cells. uild up telomeres via reverse transcription.

Question 18

Telomer shortening activates…?

Answer 18

• Activates ATM/ATR => activates p53

- Causes replicative senescence, impairs stem cell self-renewal, and induces apoptosis

Question 19

Hayflick’s limit is?

To bypass? Relation to cancer?

Answer 19

= Specific number of cell doublings before cell becomes senescent
- Mutations in p53 and Rb can bypass Hayflick limit ==> cells continue to divide resulting in complete telomere erosion and cell crisis ==> Cells overcome limit by upping telomerase activity, allowing cells to become cancerous.