Download Regulation of the Cell Cycle

Regulation of
the Cell Cycle
SBI3UP
AP Lesson
Why do cells divide?
Do all cells divide at the same rate?
Why not?
Recall the Cell Cycle:
Two Hypotheses:
1. Each event in cycle triggers the next
• Incorrect theory
2. Cell cycle is driven by specific molecular signals
• Evidence came from experiments with mammalian cells
grown in culture
The Experiment:
• 2 cells in different phases of cell cycle were fused to form a single cell with
2 nuclei
• If one original cell was in S phase and the other in G1, the G1 nucleus
entered S phase
• Known due to the chemical present in
cytoplasm
• If one original cell was in M phase and
the other in G1 the nucleus entered M phase
• Known due to formation of spindle and condensing of
chromosome
• However, the chromosomes would not be duplicated
S and G1  S phase
M and G1  M phase
What if the 1st theory was correct?
How would the results of the experiment differed?
• Experiments concluded that events of are directed by a cell
cycle control system
• Set of molecules that trigger/coordinate cell cycle events
• It operates on its own
• The control system is subject to external/internal control
Cell Cycle Checkpoints:
• Point in cell cycle where stop/go signals regulate cycle
• Signal checks that important processes have been complete
• E.g. cell size, DNA replication, spindle fiber attachment
• Checkpoints are found in G1, G2, and M phase
The G1 Checkpoint:
• G1 has been known as the “restriction point” in mammalian
cells
• If cells pass G1 checkpoint they will likely divide
• If cells don’t pass G1 checkpoint they go to G0 phase  nondividing
• E.g. nerve cells, liver cells
What if a cell ignored the checkpoint at the G1 phase?
What would be the consequences?
Molecular Basis for the Cell Cycle Clock:
• Rhythmic fluctuations
• Abundance and activity of cell cycle control molecules
Two main types of regulatory molecules (proteins):
1. Kinases
2. Cyclins
Kinases:
• Phosphorylating other proteins to
activate/inactivate them
• Give “go ahead” at G1 and G2
checkpoints
• Present in constant concentrations
• Inactive unless attached to a cyclin
• Thus known as cyclin-dependent
kinases (Cdk)
• Cdk + Cyclin  MPF
Phosphorylation is the addition of a
phosphate group to a protein.
MPF (maturation-promoting factor/M-phase promoting factor)
• Functions:
1. As kinase
 Initiates mitosis
 Contributes to chromosome condensation and spindle
formation
2. Activates other kinases
 Phosphorylates a variety of proteins
 Eg. Phosphorylates protein of the nuclear lamina
 fragmentation of nuclear envelope
4. Cdk
component of
MPF is recycled
3. One indirect effect
of MPF is the
breakdown of its own
cyclin
2. MPF promotes
mitosis by
phosphorylating
various
proteins/enzymes
1. Accumulated cyclin
molecules combine
with Cdk molecules to
produce MPF by G2
checkpoint
Internal Signals:
• M phase checkpoint
• Kinetochores not yet attached to spindle microtubules send
molecular signal
• Sister chromatids stay together, delay anaphase
• When kinetochores of all chromosomes are attached
• Anaphase-promoting complex (APC) becomes active
• Triggers breakdown of cyclin and inactivation of proteins
holding chromatids together
• Ensures right number of chromosomes in daughter cells
External Signals:
1. Chemical
• 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
2. 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
• Why?
• Physical contact (minor)
• Amount of required growth factors and nutrients available
(major)
3. Anchorage Dependence
• Requires substratum
• Eg. Inside of culture container or extracellular matrix of a tissue
• Signaled through pathways using plasma membrane proteins and
cytoskeleton
How are cancer cells different from normal cells?
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
• Cancer cells are immortal
• can divide indefinitely if given continual supply of
nutrients and an adequate environment to grow
• Eg. HeLa cells: a cultured cell line from 1951,
Henrietta Lacks’s tumour
• Vs. normal cells in culture only divide 20-50
times
Hypotheses for NO density-dependent inhibition in cancer
cells:
• 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
Transformation to Cancer Cells:
• 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 Tumours:
• 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
Treatment: Localized Tumour
• high-energy radiation
• Damages DNA in cancer cells
• normal cells can repair damage, cancer cells cannot
Treatment: 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)
Things to Know:
• Stages of the cell cycle
• Cell cycle checkpoints
• Molecular basis for cell cycle clock
• Internal/external signals
• Cancer cells: development, types of tumours, treatments