Cyclins, CKIs, ATM, ATR, and Caspases

Question 1

The components of the G1 Cdk complex

Answer 1

Cyclin D, and Cdk4 or Cdk6

Question 2

Components of the G1/S Cdk complex

Answer 2

Cyclin E, Cdk2

Question 3

Components of S Cdk complex

Answer 3

Cyclin A, Cdk1 Cdk2

Question 4

Components of the M Cdk complex

Answer 4

Cyclin B, Cdk1

Question 5

Targets of the APC

Answer 5

Securin proteins linking sister chromatids, and the S and M Cdk complexes.

Question 6

What is the function of the ATM protein family in relation to the cell cycle

Answer 6

The “Ataxia Telangiectasia Mutated” proteins. Are safety checking proteins which scan dsDNA for strand breaks.

If these ATM proteins detect DNA damage they activate DNA repair and/or apoptotic pathways via their kinase activity.

ATM activates Chk1 and Chk2 kinases, which then activate p21 and p53 (Cdk inhibitors, CKIs)

Question 7

At what points in the cell cycle are ATM proteins important?

Answer 7

Many.

At cell cycle re-entry, ie: G1 -> S or G0 -> S

From G2 -> M

Metaphase -> Anaphase

Anaphase -> Telophase

Question 8

Effects of p53

Answer 8

p53 stimulates transcription of p21

p21 binds and inhibits G1/S Cdk complex and S-Cdk complexes.

Question 9

Are cyclins expressed highly before, during, or at the end of their corresponding cell cycle phase

Answer 9

Cyclins rise just prior to the start of their indicated phase, and remain high throughout, then must fall to allow the phase to end.

Question 10

What is needed for a cyclin dependent kinase to be fully active

Answer 10

1) binding to its target cyclin

2) activation by the Cdk-Activating Kinase. CAK.

Question 11

What is the main cyclin target of mitogens, and how do mitogens regulate the cyclin levels?

Answer 11

To increase levels of G1/S Cdk complex, cyclin E.

Mitogen signal cascades phosphorylate and inactivate the inhibitory Retinoblastoma Family proteins. (RB proteins).

RB proteins then release E2F transcription factors to which they were bound.

E2F Transcription factors can then induce the G1/S and S cyclin expression.

Question 12

What are the main gene targets induces by the G1-Cdk complexes

Answer 12

The E2F family of proteins.

E2F proteins themselves then induce other G1/S and S cyclins and other initiating factors for cell cycle entry.

Question 13

What other kinases are involved in the downstream signaling of ATM and ATR proteins?

Answer 13

The Chk1 and Chk2 protein kinases.

Question 14

Initiator caspases

Answer 14

Caspase 2, 8, 9, 10

Question 15

Executioner caspases

Answer 15

3, 6, 7

Question 16

Inflammatory caspases

Answer 16

1, 4, 5

Caspase 1 was first called ICE, Interleukin-1-converting enzyme.

Question 17

How are caspases activated?

Answer 17

By proteolytic cleavage of procaspases -> active caspases.

Question 18

Targets of the initiator caspases

Answer 18

Other procaspases, both initiators to amplify the signal and executioners

Question 19

Targets of executioner caspases

Answer 19

Among their very many targets:
Nuclear Lamins 
Nuclear inhibitors of Endonucleases
Cytoskeletal proteins
Cell-Cell adhesion proteins

Question 20

What are SMACs

Answer 20

Second Mitochondria-derived Activator of Caspases.

Mitochondrial proteins that are released to the cytosol following permeation of mitochondrial membrance by caspases.

SMACS bind and inhibit IAP proteins (Inhibitors of Apoptosis)

Part of the Intrinsic Apoptosis pathway.

Question 21

Mitochondrial factors that are released to stimulate the intrinsic pathway of apoptosis.

What protein transport them across the membrane?

Answer 21

Cytochrome c

SMACs

The MAC channel Mitochondrial Apoptosis-induced Channel,

aka

The Mitochondrial Outer Membrane Permeabilization Pore.

Question 22

Downstream target of Cytochrome c in apoptosis

Answer 22

Apaf-1 and ATP, and then procaspase 9

Cytochrome c-Apaf-1-ATP complex binds to pro-caspase 9.

This is the apoptososme.

Question 23

What comprises the apoptosome

Answer 23

Cytochrome c, Apaf-1, ATP, and procaspase 9.

Question 24

What is Apaf-1

Answer 24

Apoptotic Protease Activating Factor-1

Part of the apoptosome.

Question 25

Describe the intrinsic apoptotic pathway

Answer 25

1) Mitochondria are induced to swell and/or are porated via the MAC channel.
2) Cytochrome c and SMACs are released
3) Cyctochrome c complexes with procaspase 9 and ATP,
4) This complex binds Apaf-1 forming the apoptosome.
4) Procaspase 9 is cleaved to active caspace 9 in the apoptosome.
5) Caspase 9 activates Caspace 3 molecules (and other 9’s)
6) Caspase 3 executioner caspace initates apoptosis

Question 26

What proteins can inhibit the formation of the MAC pore

Answer 26

Bcl-2 family of anti-apoptotic proteins.

Question 27

Anti-Apoptotic proteins

Answer 27

Bcl-X Bcl-2

Question 28

Pro-apoptotic, non-caspase proteins

Answer 28

BAX, BAD, BID, BAK

promote mitochondrial permeation.

Question 29

What pathway is Apoptosis Inducing Factor part of?

Answer 29

The Caspase-Independent pathway.

It is ALSO released from the mitochondria.