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Flashcards in Cell Cycle Deck (35):
1

name the different phases of the cell cycle

G1 or preparatory phase, longest phase

S phase, where DNA replication happens

G2 phase, where the cell is preparing for mitosis, checking for the right order

M phase - mitosis

Cytokinesis, cells split into two

2

endoreduplication

cells with more than 2n copies of DNA

cells go through cell cycle stopping before mitosis

replication without splitting over and over again

3

interphase

the time when the cell grows and replicates its DNA, divded into G1, S, and G2

4

cyclin-dependent kinases (Cdks)

family of 11 related protein kinases, crucial for cell cycle progression and other activities

binds to cyclins, and Cdk-cyclins only have partial kinase activity

phosphorylation of specific amino acids on the Cdks can either activate or inhibit the kinase

5

cyclins

bind to Cdks, at least 16 differeny cyclins, have varying levels during the cell cycle to dictate what happens at different points in time during the cell cycle

6

four mechanisms that regulate Cdk activity

1. Association with cyclins

2. activating phosphorylation of threonine around position 160

3. inhibitory phosphrylation of threonine 14 and 15

4. Association with Cdk inhibitors (CKIs)

7

CKI

cyclin-dependnt kinase inhibitor, along with inhibitor of Cdk4 (INK4 families bind to and activate the Cdk-cyclin complexes

some members of the CKI family also can act as positive cofactors for Cdk-cyclin assembly and activation

8

Describe the four classes of cyclins that affect Cdk activity throughout the cell cycle.

Cyclin D synthesis beings in G1 and stays relatively constant until it is degraded and disappears through mitosis

Cyclin E is the G1/S cyclin, rises at the end of G1 and rapidly decreases at the beginning of S phase

Cyclin A is important for S phase and transition through G2

Cyclin B increases throughout G2 and then drops during mitosis after it peaks

9

cyclical proteolysis of CKIs

SCF phosphorylates CKI and makes it a target for E1 and E2 ubiquitin ligase, which targets the CKI for degradation

10

cyclical proteolysis of cyclins

done by APC after an activating subunit Cdc 20

ubiquitinylates cyclin/Cdk complex

APC = Anaphase promoting complex

M-Cdk activates APC, negative feedback loop

11

three major cellc ycle checkpoints

G1/S, G2/M, and M/cytokinesis

12

cell growth signals

GSK3beta and Ras

GSK3beta inhibits formation of Cyclin D1/Cdk4, Cyclin D1/Cdk6, and Cyclin E/Cdk2

Ras promotes Cyclin D1/Cdk4 and Cyclin D1/Cdk6

13

TGFbeta

binds to a surface receptor serine-threonine kinase

signaling cascade promotes Smad3 and Smad4, which indirectly inhibits cdc25A and subsequently Cyclin D1/CDK4

Smad3/4 also indirectly inhibits p15 thorugh 19

14

differentiation signals

p15 through 19, which inhibit Cyclin D1/Dck4 formation

15

cell-cell-ECM contacts

activate GSK3beta and RhoA

GSK3beta inhibits beta-catenin/TCF, which indirectly activates Cyclin D1/Cdk6/4

RhoA indirectly inhibitis p21 and p27, which inhibit Cyclin D1/Cdk6/4 as well as Cyclin E/Cdk2

16

DNA damage

activates ATM, which activates p53, which indirectly activates p21 and p27

17

p16

indirectly inhibits Cyclin E/Cdk2

18

retinoplastoma (Rb)

a protein that binds to transcription factor of E2F

can be mildly phosphrorylated by Cyclin D/Cdk4/6

hyperphosphorylated by cyclin E/Cdk2

19

E2F

transcription factor regulated by Rb, when bound to Rb, recruits histone deacetylases to chromatin

when not bound to Rb, activates transcription of several hundred genes important for DNA synthesis and cell cycle progression

E2F is one of the genes activated, so there is a positive feedback loop

cyclin E, Cdk2, cyclin A, and other DNA replication factors are also activated

20

CIP/KIP and INK4

two families of cyclin/Cdk inhibitors that help regulate cell cycle checkpoints

21

Describe the process of Rb phosphorylation that leads to the activation of DNA replication

p27 helps promote the formation of Cyclin D/Cdk4 complexes, which gets transported to the nucleus

Cyclin D/Cdk4 mildly phosphorylates Rb, which allows the build up of cyclinE/Cdk2 through E2F release, can also soak up free-floating p27 in the nucleus

p27 in the nucleus initially inhibits Cyclin E/Cdk2 complexes, but as more Cyclin E/Cdk2 are formed and more Cyclin D/Cdk4 enters the nucleus, p27 gets phosphorylated and degraded

free Cyclin E/Cdk2 buildup can then hyperphosphorylate Rb and launch the cell into S phase

22

Descrive the two positive feedback loops related to Cyclin E/Cdk2 formation

CKI is both phosphorylated and degraded as well as sequested onto Cyclin D/Cdk4 complexes

23

myoD

a transcription factor that is the master regulator of muscle development, activates the transcription of p21, which inhibits several Cdk-cyclins

p21 also binds to the DNA replication factor PCNA, blocking the DNA replication

24

contact inhibition

a process in cells that become growded, where Cdk inhibitor p27 is upregulated in cells that are touching neighboring cells

25

control of DNA replication by S-phase cyclins

to ensure DNA replicatino only happens once per cycle, Cdc6 and Cdt1 bind to the origin recognition complex (ORC)

MCM is able to assemble in the presence of Cdc6

cyclin complexes for the S-phase promoting factor (SPF)

a build-up of Cyclin B/Cdk1 and Cyclin E/Cdk2 during  phase leads to phosphorylation of Cdc6, leading to its degradation

the assembled MCM complexes drive replication, but the ORCs are phosphorylated by the Cyclin/Cdk complxes and can no longer bind Cdc6/Cdt1 until the cycle is completed

26

geminin

prevents Cdc6/Cdt1 from loading Mcm proteins, accumulates in S phase

27

replication origin clusters

all clusters on the same chromosome fire at about the same time

about 1000 of these clusters in human cells

can be divided into "early" or "late" replicating origins

R-bands are gene-rich and early replicating

G-bands are gene poor and late-replicating

later replicating DNA is concentrated around nucleoli and near the nucelar periphery where heterochromatin is abundant

28

histone genes

transcription rises dramatically during S phase

processing increases about 10 fold

histone mRNAs are not polyadenylated, increased staability in cytoplasm during S phase

stability decreases 40-fold in G2

29

centrosome duplication

happens in S phase in preparation for the next mitosis

30

cyclin E substrates

initiation of transcription from histone gene clusters initated by Cyclin E/Cdk4

also regulates centrosome replication

Cyclin E/Cdk2 also phosphorylates NPM/B23, which releases it from the centrosome

31

cyclin H

phosphorylates the cyclin D1/Cdk/pRB complex and is necessary for full cyclin D1 activity

32

Describe the activities of the regulatory network that results from DNA damage.

ATM and ATR are the major sensing kinases that lead to phosphorylation of downstream factors, which lead to control of the cell cycle when DNA damage is detected

33

How is mitosis suppressed until DNA replication is completed?

ATR is associated with the replisome, and it actively phosphorylates CHK1, which then phosphorylates CDC25A

CDC25A gets degraded when phosphorylated by SCF, preventing the activation (dephosphorylation) of the Cyclin/Cdk2 complex

34

Describe how the HPV oncoproteins deregulate the cell cycle checkpoints

E7 binds to Rb and related E2F suppression proteins to prevent Rb control of the G1/S checkpoint

E6 binds p53 and targets it for degradation, which prevents the activation of p21, which workds to inhibit Cyclin E/A/B - Cdk2/1 complexes

35

Describe how cells enter replicative senescence and what happens when telomerase becomes involved at various points of the cell's replicative lifespan.

replicative senescence after 50-70 divisions

crisis after 80 divisions if checkpoints are lost, then telomeric crisis and death

if telomerase is activated before replicative senescence, cells become immortal

if cells are undergoing crisis and then telomerase is activated, they will become immortal with many genetic defects, often leading to cancer