2 Why It Matters Cell division: Is what got you to your present station in life25,000,000/second (hair, skin, blood cells, tissue repair, etc.)Body cannot give cells the license to decide on their own when to grow & divide
3 Cancers: failures of cell cycle The molecular actions of most oncogenes& tumor suppressor genes must be explained in termsof their effects on the cell cycle…
4 Central Governor of Growth & Proliferation Cell cycle clock is a molecular circuitry that:Processes/integrates signals from outside & inside the cellDecides whether a cell should enter active cell cycle or retreat to non-proliferating state
5 So, let’s make a new cell! Key processes: DNA replication Mechanism to separate replicated chromosomesSet of molecular controls over entire processA cast of thousands!(mostly proteins)
6 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 replicationG2: growth, prep for ÷M phase:Mitosis: nuclear ÷Cytokinesis: cytoplasmic ÷
7 Phases of Mitosis Mitosis Prophase Metaphase Anaphase Telophase Cytokinesis
8 Regulation of cell cycle Checkpoints monitor & regulate the progress of the cell cycle and impose quality controlCells undergoing cell cycle are targeted in cancer therapy (DNA is relatively exposed)
9 The Restriction point (R G1/S transition Deregulation of the R point decision accompanies the formation of most, if not all types of cancer
10 Cyclins & cyclin-dependent kinases (cdks) Cyclins: proteins that regulate activity of cdksCdks: enzymes that control the cell cycleKinases specialize in phosphorylation cascadescdks: serine/threonine kinases
11 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 –)
12 Retinoblastoma protein (pRb) & G1-S transition pRb controls passage through R pointCyclin 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).
13 Transcription Factors (TFs) There are TFs in human genomegenes are turned on over the course of the cell cycle!
14 Cancer & pRb pRb function can be impacted or lost in a variety of ways Excessive mitogenic signalsMutation of the Rb geneAction of oncoproteins that deregulate pRb phosphorylation
15 DNA mutations disrupt the cell cycle Mutations may be caused by:1. radiation2. smoking3. Pollutants4. chemicals5. viruses
16 While normal cells will stop dividing if there is a mutation in the DNA, cancer cells will continue to divide with mutation
17 Treating CancersCancer treatments include drugs that can stop cancer cells from dividing.