The Cell Cycle and Cancer

How is growth controlled? How is the Cell Cycle Regulated? Clue: cytoplasmic chemicals can signal mitosis

What tells a cell to divide? External Controls –Growth Factors Internal Controls –Cyclins –CDK –“checkpoint controls”

During the cell cycle, when does regulation take place? M G1 G2 S = DNA Damage Checkpoints = Spindle Checkpoints = G1 Checkpoint = G2 Checkpoint

Checkpoints are places in the cell cycle where a cell will be stopped so that it can be checked for mistakes. Hey buddy, I don’t care whatcha say! I am not letting you through unless your DNA is correct! Checkpoint Control

Cell Cycle Checkpoint Details

During the cell cycle, how does regulation take place? A Cascade of Protein Phosphorylations Phosphorylation = phosphate groups (PO 4 ) are added onto substrates by enzymes called kinases That guy Kinase asked me out and then told me he wanted give me a phosphate group to turn me on…ugh..men! Oh no he didn’t.

What kinase proteins control cell growth internally? CDK: always present in cells Cyclin: level varies throughout the cell cycle MPF: “mitosis promoting factor” --occurs when cyclin binds to CDK.

How does cyclin’s structure allow for its function of promoting mitosis?

What signals the kinases to stop working? Kinetochores and APC –C’somes must attach to kinetochore fibers before anaphase begins –APC (Anaphase Promoting Complex) triggers breakdown of cyclin –Ubiquitin marks cyclin for destruction -->see Fig 19.12)

Ubiquitin marks proteins for destruction

Cancer Cancer is when the cell cycle goes wrong. What might happen to cause a cell cycle to wreak havoc?

Gain-of-Function Mutations Growth Stimulating Pathway Proto-oncogenes create Ras when phosphorylated (activated) Ras relays external growth signals to nucleus which produces proteins that stimulate the cell cycle Oncogenes = too much Ras

Loss-of-Function Mutations Growth Inhibiting Pathways p53 - “guardian angel of the genome” Tumor-suppressor gene is a transcription factor that activates proteins that blocks cdk activity or initiate apoptosis

Let’s look at an example Rb P = Hypo-phosphorylated (Under-phosphorylated) Rb P P P P P = Hyper-phosphorylated (Over-phosphorylated) Retinoblastoma Protein (Rb) = an important cell cycle regulator and tumor suppressor that is controlled by how much it is phosphorylated. It is a SUBSTRATE for the enzyme Cyclin-Dependent Kinase (CDK’s).

E2F Transcription Factor: a protein that helps TRANSCRIBE genes (DNA  RNA) E2F is a transcription factor that is responsible for helping transcription of genes that help cells enter S phase E2F S-phase Gene Pretend this is a gene (piece of DNA) that needs to be transcribed to help push cells into S phase; without the transcription factor, E2F, it is NOT transcribed (no mRNA is made). S-phase Gene When E2F is allowed to “sit” on the gene, it helps the gene to undergo transcription. Copies of mRNA are made Copies of mRNA Transcription

E2F Rb and cdk’s Rb P P P P P P Cyclincdk No Transcription; No S-phase genes; No continuation through the cell cycle E2F S-phase Gene Transcription S-phase Gene S-phase genes transcribed! Let’s go start S-phase!

Cdk inhibitors E2F Rb P P P P P P Cyclincdk E2F S-phase Gene p16p21 p21 and p16 are proteins that inhibit the function of cdk’s. If you inhibit cdk function, Rb DOES NOT get hyperphosphorylated and E2F is NOT able to transcribe genes; when cdk inhibitors are around, the cell cycle is stopped!

Balance E2F Cyclin cdk p16 p21 Rb P P P P P P Checkpoint Proteins CANCER STOP GO

G0=quiescence (resting state) Add Growth Factor Remove Growth Factor Growth : a series of events coordinating the replication and division (mitosis and cytokinesis) of DNA