Cell Cycle Checkpo The cell cycle cells duplicate

Cell Cycle Checkpo

The cell cycle: cells duplicate their contents and divide

The cell cycle may be divided into 4 phases

The cell cycle triggers essential processes (DNA replication, mitosis)

Cell Cycle Checkpoints

Progression of the cell cycle is regulated by feedback from intracellular events

Major Checkpoint Monitoring Molecules • • • Cyclins Cyclin Dependent Kinases (CDKs) p 53 - DNA damage RB - Retinoblastoma APC - Anaphase Promotin Complex

Cyclin-dependent protein kinases drive progression through the cell cycle • Cyclin-dependent kinases (Cdks) are inactive unless bound to cyclins • Active complex phosphorylates downstream targets • Cyclin helps to direct Cdks to the target proteins

Cellular levels of (mitotic) M-cyclin rises and falls during the cell cycle • M-cyclin levels are low during interphase but gradually increases to a peak level during mitosis • M-cdk activity is, likewise, low in interphase but increases in mitosis

The abundance of cyclins (and the activity of Cdks) is regulated by protein degradation • M-cyclin becomes covalently modified by addition of multiple copies of ubiquitin at the end of mitosis • Ubiqutination is mediated by the anaphase promoting complex (APC) • Ubiquitination marks cyclins for destruction by large proteolytic machines called proteasome

Cdks are also regulated by cycles of phosphorylation and dephosphorylation

Cdk activates itself indirectly via a positive feedback loop

Distinct cyclins partner with distinct Cdks to trigger different events of the cell cycle

S-Cdk triggers DNA replication - its destruction ensures this happens once per cell cycle

Checkpoints ensure the cell cycle proceeds without errors

Checkpoint: DNA damage arrests the cell cycle in G 1

Checkpoint: spindle assembly • Mitosis must not complete unless all the chromosomes are attached to the mitotic spindle • Mitotic checkpoint delays metaphase to anaphase transition until all chromosomes are attached • Prolonged activation of the checkpoint -->cell death • Mechanism of many anti-cancer drugs

Cells can withdraw from the cell cycle and dismantle the regulatory machinery • G 0 is a quiescent state • Cdks and cyclins disappear • Some cells enter G 0 temporarily and divide infrequenty (I. e. hepatocytes) • Other differentiated cell types (neurons) spend their life in G 0

p 53 Anti-tumorigenic • p 53 suppresses cell replication and growth when there is DNA damage. • Impact of less that diploid complement of p 53.

p 53 Activity

Outcome of p 53 Activation • Halts cell cycle until repair is completed. • Launches cell into apoptosis (programmed cell death).

Loss of RB – Enables continuous DNA synthesis – Defects in p 16, cyclin D, Cdk 4 have same result – Found in melanoma and liposarcoma

Anaphase Promoting Complex (APC)

Checkpoint Failure

Cancer • Normal cell division: – Controlled by cell cycle checkpoints • CHECKPOINTS – critical control points that determine if a cell will move to the next portion of the cell cycle. • Cancerous cell division: – Ignores the cell cycle checkpoints • Caused by DNA mutations • Cells grow and divide out of control • Cancerous cells do not perform designated purpose. • Crowd out normal cells that do perform designated purpose.

Cell Cycle Checkpoints • G 1/S – Monitors cell size and for DNA damage • G 2/M – Replication complete, DNA damage? • M – Spindle fibers connected, etc. ? • G 0 – Does body require more of my type of cell?

Control of cell division continued: Density Dependent Inhibition: Normal cells cease dividing once critical cell density is reached. Cancer cells do not possess this trait.

Cancer is a disease of the cell cycle. Some of the body’s cells divide uncontrollably and tumors form. Tumor in Colon Tumors in Liver

While normal cells will stop dividing if there is a mutation in the DNA, cancer cells will continue to divide with mutation.

Due to DNA mutations, cancer cells ignore the chemical signals that start and stop the cell cycle. They don’t communicate with neighboring cells and continue to grow and form tumors.