Cell Cycle (Week 11)

G1/S Checkpoint

Checkpoint ensures cell has adequate nutrients and no DNA damage before replication

Cancer, Tissue

Cell cycle implications - __/angiogenesis, embryonic development, __ repair

Cdc 20, metaphase-anaphase

__ protein is responsible for APC/C activation for degrading proteins that hold sister chromatids together → Allows __-__ transition (M)

G1, S, G2

Interphase (M) Components/Phases

G1

Most responsive to external cues; “restriction point”, chromosomes decondense (Interphase)

EGF, Growth factors

External cues G1 responds to include FGF, __, and other __ __

S phase

DNA replication (Interphase)

G2

Organelles and spindles replicate, nuclear envelope dissipates (Interphase)

Dissipated, condense, spindle

Prophase (M)

• Nuclear envelope is __, chromosomes __ (condense/decondense), __ apparatus forms

Microtubules, plate

Metaphase (M)

• __ attach to each sister chromatid

• Alignment of chromosomes at equator “metaphase __”

chromatids, poles

Anaphase (M)

• Anaphase A: Sister __ move apart as microtubules shorten

• Anaphase B: __ move further apart

Spindle, reforms, decondense

Telophase (M)

• __ apparatus dissociates, Nuclear envelope __

• Chromosomes __ and cytokinesis

Cyclin-Dependent Kinases (CKDs)

__ __ __ phosphorylate target proteins

• Present throughout cycle, specific to different phases

Cyclins, synthesis, proteasome

__ bind and activate CDKs

• Concentration increases as regulated; no enzymatic activity

• Controlled by protein __ and degradation by __

D, E, A, B

• Cyclin _ has G1-Cdk complex

• Cyclin _ has G1/S-Cdk complex, also acts as the restriction point

• Cyclin _ has S-Cdk complex

• Cyclin _ has M-Cdk complex

D

Cyclin _ has G1-Cdk complex

E

Cyclin _ has G1/S-Cdk complex, also acts as the restriction point

A

Cyclin _ has S-Cdk complex

B

Cyclin _ has M-Cdk complex

p27, p21

CDK-Cyclin Inhibitors (2)

Ubiquitin, proteases

• __ is a post-translational modification of proteins targeting for proteasomal degradation

  • Target protein is degraded using __ inside proteasome

D, Rb, G1

G1 → S (Step 1)

• Transcription of Cyclin _

• Binds to G1-CDK complex → Phosphorylates __ protein

• Allows progression to Late __ phase

Rb, E2F, E

G1 → S (Step 2)

• __ protein phosphorylated by G1/CDK complex

• Releases bound __ transcription factor

  • Begins transcription of S phase protein genes

• Cyclin _ transcribed binds to G1/S CDK

E, 27, S

G1 → S (Step 3)

• At restriction point - Increased Cyclin _ and decreased p__ activity

• Full Cyclin E - G1/S CDK activation

  • Progression to _ phase

B, mitosis, M-CDK, cdc25

G2 → M

• Cyclin _ synthesized and binds to M-CDK

• Complex phosphorylates target proteins for early __ process

• Inactive Cyclin B/__ complex stockpiled until M phase starts

• When ready __ (protein) removes inhibitory P → Activates complex

Anaphase, positive, G1

M → G1

• APC (__-promoting complex): Targets Cyclin B for ubiquitination and degradation by proteasome

  • Ends __ (+/-) feedback for mitosis → Cell proceeds to __ phase

G1, G2, meta-ana

3 Cell Cycle Major Checkpoints

• __ - Growth factor presence, DNA damage

• __ - Completed DNA replication, DNA damage

• __ to __ - Chromosomal attachment to separate spindle fibers via kinetochores

Rb

Protein that holds onto E2F growth factor keeping it inactive → prevent uncontrolled division

p53

Transcription factor/protein that increases p21 synthesis by binding to promoter region

Repair, apoptosis, mutated

• p53 mechanism allows for pausing of cell cycle, and for DNA __

  • If no repair is allowed, p53 increases transc. factors for __ (event)

  • This protein is the most __ protein in cancer patients

G1

__ checkpoint dysfunction = Cancer’s proliferated growth of immature cells

G2

__ checkpoint dysfunction = Cancer’s genomic instability → Passing on damaged cell traits and mutations to daughter cells

Meta-Ana

__ __ checkpoint dysfunction = Cancer’s aneuploidy with having incorrect number of chromosomes → Encourage mutations

p53, Rb

HPV 16 and 18 are related to cancer proliferation

• E6: ubiquitin degradation of __

• E7: downregulate __, upregulate E2F transcription

Cisplatin

DNA damage, cell cycle arrest, apoptosis (cancer tx)

Taxol

Loss of microtubule dynamics, spindle checkpoint, apoptosis (cancer tx)