Cell cycle part 2

P53 inactivated by what

Point mutations

p53 mutations

only 1 (missense) mutation is needed to inactivate the p53 tetramer

p53 haplo

p53 is haploinsufficient

RB haplo

RB is haplosufficient bc losing 1 doesn’t change its function

p53 knock-in point mutation experiment

wild type and mutated type alleles present will inhibit the p53 function

p53 knock-in deletion experiment

wild type and null alleles present is almost normal p53 function

tumor suppressor 2 hit model

loss of tumor suppressor function need BOTH copies to be deleted (p53 is exception)

ARF and p53

E2F regulates ARF which inhibits MDM2 which activates p53

What happens in G1/S checkpoint

In response to stress p53 induces expression of p21

Degradation of Cdc25 phosphatase

what is p53 targeting in G1/S checkpoint

CDK 2 and 1 complexes

what does degradation of Cdc25 phosphatase in G1/S checkpoint do

Cdc25 removes inhibitory phosphates on CDKs, so degrading inhibits cell cycle

what is p21

a CDK inhibitor

how does inhibiting CDK 2 during G1/S affect cell cycle progression?

You are going to pause progression

what happens in G2/M checkpoint

ATM and ATR activated they activate p53 and checkpoint kinases

checkpoint kinases degrade CDC25 or phosphorylate p53

p21, 1433, GADD45 complex upregulated

what does 1433 complex do?

binds to phosphorylated CDC2 or CDK1 and results in its nuclear export

also sequesters CDC 25

what does GAD45 do

Binds to cyclin B, CDK1 complexes and breaks their interaction

inhibits bc CDKS need cyclins to be activated

What happens in S phase checkpoint

911 complex activates ATM which activates Chk2 which inhibits CDC25A

No p53

does not completely halt cell like the other checkpoints (gradual slowdown instead)

When are cells responsive to mitogenic growth factors and TGFB?

During G1

Cyclin B pairing

With CDC2/CKD1

Cyclin D pairing

CDK4/6

Cyclin E pairing

CDK2

Cyclin A pairing

CDK2 and CDC2/CDK1

When is cyclin B active

M phase

When is cyclin D active

G1

When is cyclin E active

Late G1

When is cyclin A active

CDK2 in S

CDC2/CDK1 in S and G2