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LAQ > Cell Growth and Differentiation > Flashcards

Cell Growth and Differentiation Flashcards

1
Q

What important protein regulates the progression of cells through the G1 checkpoint?

How does it do this?

A

Retinoblastoma Protein

Binds to E2F -> stimulates S-phase protein expression.

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2
Q

What happens when Rb after it is phosphorylated by ___ and ___?

A

When Rb is phosphorylated by cyclin D-CDK4 and Cyclin E-CDK2, it can no longer bind to E2F and the cell is consequently allowed to progress to the S phase. DNA replication will consequently start.

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3
Q

What proteins do the target genes of E2F include?

A

Cyclin E and S phase proteins including DNA polymerase, thymidine kinase and PCNA (protein involved in DNA replication).

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4
Q

What are G1 CDKs activated in response to?

A

• G1 CDKs are activated in response to environmental signals, late CDKs by preceding kinase activities.

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5
Q

What is RB hyperphosphorylated dephosphorylated by?

A

Protein phosphatase 1

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6
Q

G1 CDKs ___ and late CDKs ___.

A

G1 CDKs hypophosphorylate, and late CDKs hyperphosphorylate.

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7
Q

Unphosphorlyated RB binds to __ transcription factor and what does this prevent?

A

Its stimulation of S-phase protein expression.

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8
Q

What does released E2F stimulate?

A

Expression of more cyclin E and S-phase proteins e.g. DNA polymerase, thymidine kinase, PCNA etc. DNA replication starts.

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9
Q

Overview:
What does Rb control and when?
What can cyclin-CDK phosphorylate and what effect does this have?

A
  • Rb controls cell cycle in all cells, when hypophophorylated/unphosphorylated it binds to E2F transcription factor
  • Cyclin-CDK can phosphorylate RB, releasing E2F leading to expression of Cyclin E and other S phase proteins
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10
Q

Growth factor signalling activates?

A

Early gene expression (transcription factors – FOS, JUN, MYC)

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11
Q

What do early gene products stimulate?

A

Early gene products stimulate delayed gene expression (includes Cyclin D, CDK2/4 and E2F transcription factors)

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12
Q

What is E2F sequestered by?

A

• E2F sequestered by binding to unphosphorylated retinoblastoma protein (RB)

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13
Q

What do G1. cyclin-CDK complexes do to RB?

What does G1/S cyclin-CDK complexes do to RB?

A

G1 cyclin-CDK complexes hypophosphorylate RB and then G1/S cyclin-CDK complexes hyperphosphorylate RB releasing E2F

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14
Q

What does E2F stimulate the expression of?

A

E2F stimulates expression of more Cyclin E and S-phase proteins (e.g. DNA polymerase, thymidine kinase, Proliferating Cell Nuclear Antigen etc.)

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15
Q

What do S phase cyclin-CDK and G2/M cyclin-CDK complexes do?

What are these switches activated by?

A

• S-phase cyclin-CDK and G2/M cyclin-CDK complexes build up in inactive forms.

These switches are activated by post-translational modification or removal of inhibitors, driving the cell through S-phase and mitosis.

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16
Q

What happens when there is DNA damage?

A
  • Stop the cycle- by (cyclin dependent kinase inhibitors, CHEK2 etc.)
  • Attempt DNA repair- (nucleotide or base excision enzymes, mismatch repair etc.)
  • if repair impossible Programmed Cell Death (BCL2 family, caspases)
17
Q

What is DNA damage is detected at checkpoint during DNA repair?

A

• If DNA damage is detected at a checkpoint, the cell arrests and there is also an attempt to repair the damaged DNA.

18
Q

If DNA is fully repaired what happens to the cell?

A

• If the DNA is fully repaired, the cell re-enters the cell cycle whilst if complete repair is not achieved, the cell undergoes apoptosis so as not to transmit mutated DNA to daughter cells.

19
Q

When DNA is intact what happens to the TP53 gene?

A

When DNA is intact the TP53 gene is continuously destroyed by a proteosome.

20
Q

When DNA is damaged (e.g. by __) what is activated?

A

• When DNA is damaged by e.g. mutagens this activates kinase activation

21
Q

What will kinase phosphorlyate and what is the effect of this?

A

Kinase will phosphorylate the TP53 gene so it can no longer be destroyed by the proteosome and become activated and conduct the following actions

• Actions of TP53:
o Expression of CKI: cause Cell cycle arrest
o Repair not possible: Apoptosis
o DNA Repair e.g.Excision repair- so can then return to cell cycle

22
Q

What mutations are the most frequent in cancer?

A

TP53 in Cancer

• TP53 loss-of-function mutations are amongst the most frequent in cancer

23
Q

Describe the roles of TP53.

A

Prevent cell cycle arrest- faster growth
• Prevent apoptosis- so cells don’t die
Prevent DNA repair- more mutations.

24
Q

Why does preventing DNA repair cause more mutations?

A

Prevent DNA repair- more mutations
o more heterogeneity
o more adaptation
o cancer progression

25
Q

What is chemotherapy?

A

Chemotherapy

• Traditional chemotherapeutic drugs act on the cell cycle

26
Q

What is the objective of chemotherapy?

A

• Objective: stop proliferation, induce apoptosis

27
Q

What is the role of S-phase drugs?

A

S-phase drugs cause DNA damage.

28
Q

Give examples of S-phase drugs and describe what they do?

A 
5-fluorouracil (prevents synthesis of thymidine)
o	Cisplatin (binds to DNA causing damage and blocking repair)
29
Q

What do M-phase drugs target?

A

• M-Phase drugs target the mitotic spindle

30
Q

Give examples of M-phase drugs and their role.

A

Vinca alkaloids- stabilize free tubulin, prevent microtubule polymerization, arrest cells in mitosis
o Paclitaxel (Taxol)- stabilizes microtubules, preventing de-polymerization, arrests cell in mitosis
• Not just cancer: colchicine (similar mode of action to vinca alkaloids) is used for immune-suppression

31
Q

Summary:

What does growth factors binding to receptors induce?

What does G1 and G1/S cyclin-CDK complexes do?

What does release of E2F stimulate?

What happens next?

If all DNA is replicated what do G2/M cyclin-CDK complexes cause?

What happens if chromosomes are aligned on spindle?

If process fails what does TP53 initiate?

A
  • Growth factors binding to receptors induce gene expression
  • G1 and G1/S Cyclin-CDK complexes phosphorylate RB in the absence of inhibition by CKIs (expression of these is regulated by TP53 or TGF)
  • E2F released, stimulating expression of genes required for S-phase
  • Cell replicates DNA (expression of S-phase Cyclin-CDK complexes)
  • If all DNA replicated, G2/M Cyclin-CDK complexes cause cell to enter mitosis. If chromosomes aligned on spindle, exit from mitosis is triggered
  • If process fails, TP53 initiates apoptosis

LAQ (13 decks)

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