Cell Cycle, Cell Division and Apoptosis; Reading: Chapter 18

M, G1, s, G2, (interphase)

G1 check point G2 check point and M checkpoint

G0 quiescence (what clels permanently withdraw from teh cell cycle)

means that the cell dosen’t do anything

• this reserves energy;

• the cells will renter the cell cycle when conditions are right

• neurons permenatly withdraw from the cell cycle and remain in G0

• Cyclins: do not have intrinsic kinase activity, bind and activate Cdk proteins, levels fluctuate during the cell cycle

• Cdk: Cyclin-dependent kinase proteins that trigger cell cycle events when activated

cyclin-Cdk complex (what does the cyclin do specifically)

phosphorylates key proteins in the cell that are required to initiate cell cycle

• cyclin also helps direct Cdk to target proteins

Cdk concentration

does not change

what different cyclin CDK complexes

regulation of S cyclin-cdk by p27

• p27 cdk inhibitor delays the progression from G1—>S

• binding of p27 prevents Cdk from phosphorylating its target

• controlled by mitogen —> no mitogen high p27

mitogens

Mitogens are signals (usually proteins) that tell cells to divide; they activate the synthesis of G1/S cyclins

• extracellualar signals

Mitogens stimulation of S phase and proliferation

• Rb binds and inhibits transcription regulators

1) Rb is inactivated by G1 and G1/S-Cdks phosphorylation to Rb

2) the regulator is released and binds to the gene to transcribe

Check points at each phase

G1 to S transition: DNA damage can arrest cell cycle

1) DNA damage activation of p53

2) p53 binds to activate the gene for p21

3) p21 binds to S-Cdk and G1/S-Cdk to block cell entry

4) arrest in G1

G1 to S transition: Initiation of DNA replication

occurs in two steps

• origin recognition complex binds origin of replication throughout the cell cycle

  • cdc6 g1 binds to ORC

  • helicase recruited

• S-Cdk accumulation activates helicase and recruitment of DNA polymerase ; phosphorylates Cdc6 which is targeted for degradation

regulation of M cyclin-CDK and phosphatases role (what does phosphatase do)

• M cyclin accumulates late G2 and reaches max in early M stage

1) activating phosphatase removes 2 inhibitory phosphates from Cdk

2) Cdk goes on to phsophorlate —> induces chromosome condensation, formation of spindle, nuclear lamina and pores phosphorlyated cases the nuclear envelope to break down

Activated M-Cdk (positive feedback loop)

M-Cdk is able to activate more Cdc-25 which activates more M-cdk

cdc25

(CDC25 is a phosphatase enzyme)

APC = anaphase promoting complex

APC = anaphase promoting complex

• covalently attaches ubiquitin chains to S and M cyclins

• ubiquitin tags the cyclin for degradation by the proteasome

Centromere

• heterchromatin ; contains repeated base sequences

Prophase: cohesin reains only at the centromere

• S phase, protein cohesin is assembled along the lengths of the chromatids

• kinase dissemble cohesion rings everywhere except for the centromeres

• Cohesin holds the duplicated chromatids together until their separation anaphase.

Prophase: Condensins help condense chromosomes (when)

• in late G2, M-Cdk phosphorlyates codensin assembles on to DNA and helps condense the DNA

replication of centrioles and centrosomes

• G1 centrosomes contains a pair of centrioles

• s phase = centrosomes and centrioles duplicate ; the daughters remain together until mitosis

• early M = centrosomes nucleate microtubules, pushing them apart

• centrosomes form poles

Microtubule instability, centrosomes and the

mitotic spindle

Spindle microtubules are shorter and less stable than cytoplasmic

microtubules

2 classes of microtubules make up spindle

astral microtubules, kinetochore microtubules, and interpolar microtubules.

d

Mitotic spindle form (where ar ethe minus and plus ends; what does kinesin do?)

• 2 centrosomes

• minusends adjacent to the centrosomes

• grwos and shrinks dynamically

• At the zone of overlap, interpolar microtubules from opposite poles

interact via a bipolar kinesin molecule (figure at right) that connects

interpolar microtubules and moves to their + ends.

• Kinesin slides the microtubules past each other - pushing apart the

poles. Addition of tubulin to maintain overlap

Kinetochores form on the centromeres

• • Kinetochores are protein plaques that are assembled in prophase.

This arrangement allows kinetochore microtubules to polymerize and

• Microtubule-binding proteins (blue) originate from the kinetochore and attach

  to the kinetochore microtubules

depolymerize while they remain attached to the kinetochore.

Prometaphase: Fully formed Mitotic Spindle

Metaphase: Chromosomes aligned at equator

Anaphase

anaphase promoting complex destroys cohesin and the

chromatids separate - each is now termed a chromosome

The anaphase promoting complex (APC) destroys cohesins

and chromatids separate

1) APC tages inhibitory protein with ubiquitin cuasing securin to break down

2) activates proteolytic enzyme seperase breaks down cohesion

3) spindle pulls it apart

anaphase A

anaphase A, kinetochore microtubules depolymerize at both ends;

this shortening pulls the chromosomes to the poles.

Anaphase B

1) bipolar kinesin causes sliding between non-kinetochore microtubules: this pushes apart the poles.

2) A bipolar kinesin The heads move along the microtubules to the plus ends.

• Tubulin heterodimers are added to the plus ends of non-kinetochore microtubules to maintain the overlap between them as they push apart the poles

why is tublin added

to the plus ends of non-kinetochore microtubules to maintain the overlap between them as they push apart the poles

Astral microtubules pull the poles apart

Astral microtubules contact with the plasma membrane pull apart the poles using dynein.

Telophase: Reformation of nucleus

• APC destroys M cyclin (m cyclin breaks down the huclear lamina thru phsophorlyation)

• dephosphorlyation ocurres —> nuclear lamina, envelope and pores to

  reassemble in telophase, and many microtubules to disassemble, de condensation of chromosomes

Cytokinesis: Cleavage furrow occurs at central spindle (RhoA and actin and myosin)

• Left: Proteins are recruited to non-kinetochore microtubules that

activate RhoA

• RhoA drives the formation of contractile actin filaments

• Middle: Actin and myosin-II comprise the contractile ring which is

assembled immediately below the plasma membrane.