Cell Cycle and Regulation III PDF

Cell cycle and Regulation III Concept 12.3: The eukaryotic cell cycle is regulated by a molecular control system The frequency of cell division varies with the type of cell These differences result from regulation at the molecular level Cancer cells manage to escape the usual controls on...

Cell cycle and Regulation III Concept 12.3: The eukaryotic cell cycle is regulated by a molecular control system The frequency of cell division varies with the type of cell These differences result from regulation at the molecular level Cancer cells manage to escape the usual controls on the cell cycle The Cell Cycle Control System The cell cycle appears to be driven by specific chemical signals present in the cytoplasm Some evidence for this hypothesis comes from experiments in which cultured mammalian cells at different phases of the cell cycle were fused to form a single cell with two nuclei  Figure 12.14 Experiment Experiment 1 Experiment 2 Do molecular signals in the cytoplasm S G1 M G1 regulate the cell cycle? Results S S M M G1 nucleus G1 nucleus began immediately entered mitosis without S phase and DNA chromosome was synthesized. duplication. Conclusion Molecules present in the cytoplasm control the progression to S and M phases.  The sequential events of the cell cycle are directed by a distinct cell cycle control system, which is similar to a clock The cell cycle control system is regulated by both internal and external controls The clock has specific checkpoints where the cell cycle stops until a go-ahead signal is received Figure 12.15 G1 checkpoint Control system S G1 M G2 M checkpoint G2 checkpoint The Cell Cycle Clock: Cyclins and Cyclin-Dependent Kinases Two types of regulatory proteins are involved in cell cycle control: cyclins and cyclin-dependent kinases (Cdks) The activity of a Cdk rises and falls with changes in concentration of its cyclin partner MPF (maturation-promoting factor) is a cyclin-Cdk complex that triggers a cell’s passage past the G2 checkpoint into the M phase Figure 12.16 S 1 G M G1 S G2 M G1 S G2 M G1 Cdk MPF Cyclin activity concentration M Degraded G2 cyclin Cdk Cyclin is degraded MPF Cyclin G2 Time checkpoint (a) Fluctuation of MPF activity and cyclin (b) Molecular mechanisms that help regulate concentration during the cell cycle the cell cycle  Figure 12.16 1. Cyclin starts to accumlate during late S phase. Cyclin amount increases as degradation of cyclin decreases. 2. cyclin binds to Cdk activating the enzyme. MPF forms. When enough MPF accumulates, cell passes thru S 1 G Cdk G2 checkpoint. M Degraded G2 3. MPF promotes mitosis by cyclin Cdk Cyclin is phosphorylating various proteins. degraded Cyclin MPF MPF activity highest during G2 checkpoint metaphase. (b) Molecular mechanisms that help regulate 4. During anaphase cyclin is degraded, the cell cycle terminating M phase. The cell enters G1. During G1 cdk is recycled. Roles of MPF during mitosis: 1) Phosphorylates a variety of proteins, initiating mitosis. 2) Acts both directly as a kinase and indirectly by activating other kinases. 3) Promotes fragmentation of the nuclear envelope by causing phosphorylation of various proteins of the nuclear lamina. 4) Contributes to chromosome condensation and spindle formation during prophase. 5) Controls cell’s passage through the G2 checkpoint. Stop and Go Signs: Internal and External Signals at the Checkpoints Many signals registered at checkpoints come from cellular surveillance mechanisms within the cell Checkpoints also register signals from outside the cell Three important checkpoints are those in G1, G2, and M phases  For many cells, the G1 checkpoint seems to be the most important If a cell receives a go-ahead signal at the G1 checkpoint, it will usually complete the S, G2, and M phases and divide If the cell does not receive the go-ahead signal, it will exit the cycle, switching into a nondividing state called the G0 phase e.g. Nerve cells, muscle cells. Figure 12.17 G1 checkpoint G0 G1 G1 Without go-ahead signal, With go-ahead signal, cell enters G0. cell continues cell cycle. G1 S (a) G1 checkpoint M G2 G1 G1 M G2 M G2 M checkpoint G2 Anaphase checkpoint Prometaphase Metaphase Without full chromosome With full chromosome attachment, stop signal is attachment, go-ahead signal received. is received. (b) M checkpoint  An example of an internal signal is that cells will not begin anaphase until all chromosomes are properly attached to the spindle at the metaphase plate This mechanism assures that daughter cells have the correct number of chromosomes  External factors that influence cell division include specific growth factors Growth factors are released by certain cells and stimulate other cells to divide Platelet-derived growth factor (PDGF) is made by blood cell fragments called platelets PDGF signals cells by binding to a cell-surface receptor tyrosine kinase Figure 12.18-1 Scalpels 1 A sample of human connective tissue is cut up into small pieces. Petri dish Figure 12.18-2 Scalpels 1 A sample of human connective tissue is cut up into small pieces. Petri dish 2 Enzymes digest the extracellular matrix, resulting in a suspension of free fibroblasts. Figure 12.18-3 Scalpels 1 A sample of human connective tissue is cut up into small pieces. Petri dish 2 Enzymes digest the extracellular matrix, resulting in a suspension of free fibroblasts. 3 Cells are transferred to culture vessels. 4 PDGF is added to half the vessels. Figure 12.18-4 Scalpels 1 A sample of human connective tissue is cut up into small pieces. Petri dish 2 Enzymes digest the extracellular matrix, resulting in a suspension of free fibroblasts. 3 Cells are transferred to culture vessels. 4 PDGF is added to half the vessels. 10 µm Without PDGF With PDGF Cultured fibroblasts (SEM)  In density-dependent inhibition, crowded cells will stop dividing Most cells also exhibit anchorage dependence—to divide, they must be attached to a substratum Density-dependent inhibition and anchorage dependence check the growth of cells at an optimal density Cancer cells exhibit neither type of regulation of their division Figure 12.19 Anchorage dependence: cells require a surface for division Density-dependent inhibition: cells form a single layer Density-dependent inhibition: cells divide to fill a gap and then stop 20 µm 20 µm (a) Normal mammalian cells (b) Cancer cells Loss of Cell Cycle Controls in Cancer Cells Cancer cells do not respond normally to the body’s control mechanisms Cancer cells may not need growth factors to grow and divide They may make their own growth factor They may convey a growth factor’s signal without the presence of the growth factor They may have an abnormal cell cycle control system They are immortal. E.g HeLa cells since 1951  A normal cell is converted to a cancerous cell by a process called transformation Cancer cells that are not eliminated by the immune system form tumors, masses of abnormal cells within otherwise normal tissue If abnormal cells remain only at the original site, the lump is called a benign tumor  Malignant tumors invade surrounding tissues and can metastasize, exporting cancer cells to other parts of the body, where they may form additional tumors Localized tumors may be treated with high-energy radiation, which damages the DNA in the cancer cells To treat metastatic cancers, chemotherapies that target the cell cycle may be used. E.g. Drug named Taxol freezes the mitotic spindle by preventing microtubule depolymerization. Figure 12.20a Tumor Glandular tissue 1 A tumor grows 2 Cancer cells invade 3 Cancer cells from a single neighboring tissue. spread through cancer cell. lymph and blood vessels to other parts of the body. Figure 12.20b Metastatic Lymph tumor vessel Blood vessel Cancer cell 3 Cancer cells spread 4 A small percentage through lymph and of cancer cells may blood vessels to other metastasize to parts of the body. another part of the body.  Recent advances in understanding the cell cycle and cell cycle signaling have led to advances in cancer treatment Coupled with the ability to sequence the DNA of cells in a particular tumor, treatments are becoming more “personalized”