AP: Cell Cycle Regulation

Cell Cycle 2 crucial factors for normal growth: Timing and rate of cell division Cell division frequency depends on cell type: skin cells: frequently Liver cells: can divide when needed (eg. Repair a wound) Mature nerve cells, muscles: do not divide

What drives the cell cycle? Hypotheses: Each event in the cycle triggers the next incorrect Cell cycle is driven by specific molecular signals Evidence came from experiments with mammalian cells grown in culture

Cell cycle is driven by specific molecular signals

Cell cycle control system A cyclically operating set of molecules in the cell Triggers and coordinates key events in the cell cycle Regulated at certain checkpoints Regulated by both internal and external controls

checkpoints Signals transmitted by signal transduction pathways Built-in stop signals: stop cell cycle at checkpoints Overridden by go-ahead signals Signals report if crucial cellular processes completed correctly Also register signals from outside the cell 3 major checkpoints: G1, G2 and M

G1 checkpoint Restriction point in mammalian cells Most important if pass, usually complete whole cycle If no go-ahead signal  G0 phase Most human body cells in G0 phase Can called back from G0 phase by external cues (eg. growth factors)

The Molecular basis for the cell cycle clock Rhythmic fluctuations Abundance and activity of cell cycle control molecules Two main types of regulatory molecules (proteins): Kinases Cyclins

kinases enzymes that phosphorylate other proteins to active/inactive them Specific kinases give the go-ahead signals at G1 and G2 checkpoints Constant concentration Inactive unless attached to a cyclin Thus known as cyclin-dependent kinases Cdk + Cyclin  MPF

MPF maturation-promoting factor/M-phase promoting factor Functions: as kinase Initiates mitosis Contributes to chromosome condensation and spindle formation Activates other kinases Phosphorylates a variety of proteins Eg. Phosphorylates protein of the nuclear lamina  fragmentation of nuclear envelope

Self-regulation of MPF During anaphase, MPF initiates destruction of its own cyclin Cdks persist as inactive form

Internal signal at checkpoints M phase checkpoint Kinetochores not yet attached to spindle microtubules send molecular signal  Sister chromatids stayed together, delay anaphase When kinetochores of all chromosomes are attached Inactive protein holding sister chromatids Sister chromatids separate (anaphase) Ensures right number of chromosomes in daughter cells

External chemical signal Cells in culture cannot divide if missing an essential nutrient Eg. Growth factor Mitogen: a growth factor protein that promotes mitosis Eg. Platelet-derived growth factor (PDGF) Required for division of fibroblasts Fibroblast: a type of connective tissue cell with PDGF receptors Binding allows cell to pass the G1 checkpoint and divide Injury  platelets release PDGF

External physical signal: Density-dependent inhibition Crowded cells stop dividing Cultured cells form a single layer on inner surface of container If cells are removed, cells bordering space will divide to fill in Reasons: Physical contact (minor) Amount of required growth factors and nutrients available (major)

External physical signal: Anchorage dependence Requires substratum Eg. Inside of culture container or extracellular matrix of a tissue Signaled through pathways using plasma membrane proteins and cytoskeleton

Cancer cells Do not respond normally to body’s control mechanisms No density-dependent inhibition No anchorage dependence Divide excessively Invade other tissues  may kill organism Stop dividing at random points in the cycle, instead of at checkpoints Immortal: can divide indefinitely if given continual supply of nutrients Eg. HeLa cells: a cultured cell line from 1951, Henrietta Lacks’s tumour Vs normal cells in culture only divide 20-50 times

Cancer cells Hypotheses for NO density-dependent inhibition: Do not need growth factors to grow and divide May make a required growth factor themselves Abnormal signal pathway to convey GF’s signal even in its absence Abnormal cell cycle control system

Cancer cells - Transformation process that converts a normal cell to a cancer cell Escape destruction from body’s immune system Forms tumour (a mass of abnormal cells within otherwise normal tissue) If remain at original site  benign tumour (no serious problem, can be completely removed by surgery) If becomes invasive to impair functions of one/more organs  malignant tumour (cancer)

Malignant tumour (cancer) Excessive proliferation Unusual number of chromosomes (cause or effect?) Metabolism may be disabled No constructive function Abnormal changes on cells’ surfaces  lose/destroy attachment to neighboring cells and extracellular matrix Can spread into nearby tissues Can secrete signal molecules to cause blood vessels to grow toward the tumour

metastasis a few tumour cells separate from original tumour enter blood/lymph vessels travel to other parts of body proliferate and form a new tumour

Treatments – localized tumour high-energy radiation Damages DNA in cancer cells normal cells can repair damage, cancer cells cannot

Treatments - Metastatic tumour chemotherapy through circulatory system Interfere with specific steps in cell cycle Eg. Taxol prevents microtubule depolymerisation freezes mitotic spindle stops actively dividing cells at metaphase Side effects due to drug’s effect on normal cells Nausea (intestinal cells) hair loss (hair follicle cells) susceptibility to infection (immune system cells)

Taking it further Transformation always involves alteration of genes that affects the cell cycle control system