The Cell Cycle

Why It Matters Cell division: Is what got you to your present station in life 25,000,000/second (hair, skin, blood cells, tissue repair, etc.) Body cannot give cells the license to decide on their own when to grow & divide

Cancers: failures of cell cycle The molecular actions of most oncogenes & tumor suppressor genes must be explained in terms of their effects on the cell cycle…

Central Governor of Growth & Proliferation Cell cycle clock is a molecular circuitry that: Processes/integrates signals from outside & inside the cell Decides whether a cell should enter active cell cycle or retreat to non-proliferating state

So, let’s make a new cell! Key processes: DNA replication Mechanism to separate replicated chromosomes Set of molecular controls over entire process A cast of thousands! (mostly proteins)

Phases of cell cycle Interphase: Gap 0 (G0): resting phase; no division (e.g., neurons) G1: growth, prep for DNA synthesis (e.g., enzymes) S: DNA replication G2: growth, prep for ÷ M phase: Mitosis: nuclear ÷ Cytokinesis: cytoplasmic ÷

Phases of Mitosis Mitosis Prophase Metaphase Anaphase Telophase Cytokinesis

Regulation of cell cycle Checkpoints monitor & regulate the progress of the cell cycle and impose quality control Cells undergoing cell cycle are targeted in cancer therapy (DNA is relatively exposed)

The Restriction point (R point) @ G1/S transition Deregulation of the R point decision accompanies the formation of most, if not all types of cancer

Cyclins & cyclin-dependent kinases (cdks) Cyclins: proteins that regulate activity of cdks Cdks: enzymes that control the cell cycle Kinases specialize in phosphorylation cascades cdks: serine/threonine kinases

Pattern of cyclin-cdk activity Cyclin D: 1st cyclin produced (in response to growth factors); binds to cdks 4/6 Cdks phosphorylate t target proteins (+ or –)

Retinoblastoma protein (pRb) & G1-S transition pRb controls passage through R point Cyclin D-cdks 4/6 phosphorylates pRb which then activates transcription factor(TFs), proteins involved in “turning on” genes (e.g., other cyclins DNA polymerase, etc).

Transcription Factors (TFs) There are 2000-3000 TFs in human genome 800-1200 genes are turned on over the course of the cell cycle!

Cancer & pRb pRb function can be impacted or lost in a variety of ways Excessive mitogenic signals Mutation of the Rb gene Action of oncoproteins that deregulate pRb phosphorylation

DNA mutations disrupt the cell cycle Mutations may be caused by: 1. radiation 2. smoking 3. Pollutants 4. chemicals 5. viruses

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

Treating Cancers Cancer treatments include drugs that can stop cancer cells from dividing.