The Cell Cycle
The Cell Cycle KEY CONCEPT Cells have dis2nct phases of growth, reproduc2on, and normal func2ons.
What is cell cycle? • Cell cycle is defined as a period from the end of one division to the beginning of next division of a prolifera
The Cell Cycle Your body cells go through a cycle too. This cycle allows new cells to be created to heal or replace dead or damaged cells.
Cell division
never 1 year 4 months 2 weeks 12 hours 1.5 to 3 hours 90 minutes
• Some cells are unlikely to divide (G0).
The cell cycle • The cell cycle for prokaryo
How is the eukaryo
Interphase • The stage between two successive cell divisions (the ‘holding’ stage). • Some 90 % of a cell's
Parts of Interphase • G1 Phase – Growing – Synthesize new proteins and organelles – Doing their jobs – Longest phase of cell cycle • S Phase – Chromosomes(DNA) are replicated – Key proteins associated with replica
What happens during the M phase of the eukaryo
What are the steps of mitosis? • Mitosis consists of four steps: Prophase Metaphase Anaphase Telophase
Cytokinesis Cytoplasmic division and other changes exclusive of nuclear division that are a part of mitosis or meiosis. -‐
Regulation of the Cell Cycle
The Cell Cycle Control System • The sequen
Defini
n
Cell cycle is a highly ordered process: the ini
G1 checkpoint
Control system
G1
M
M checkpoint G2 checkpoint
G2
S
Control of the Cell Cycle The cell cycle is controlled at three checkpoints: 1. G1/S checkpoint -‐the cell “decides” to divide
2. G2/M checkpoint -‐the cell makes a commitment to mitosis 3. late metaphase (spindle) checkpoint -‐the cell ensures that all chromosomes are ahached to the spindle 24
Regula
E.g. Oocytes
• can sister chroma
• has DNA synthesis been completed correctly? • commitment to mitosis
• can DNA synthesis begin? Differentiating cells
• For many cells, the G1 checkpoint seems to be the most important one • 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
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G0 G1 checkpoint
G1 If a cell receives a go-‐ahead signal at the G1 checkpoint, the cell con2nues on in the cell cycle.
G1 If a cell does not receive a go-‐ ahead signal at the G1 checkpoint, the cell exits the cell cycle and goes into G0, a nondividing state.
Examples of checkpoints in the cell cycle
Stop and Go Signs: Internal and External Signals at the Checkpoints • An example of an internal signal is that kinetochores not ahached to spindle microtubules send a molecular signal that delays anaphase • Some external signals are growth factors, proteins released by certain cells that s
How do cells know when to divide and when not to? • Internal regulators – are proteins that respond to events inside the cell. – Some proteins make sure cells do not enter mitosis un
• Two types of regulatory proteins are involved in cell cycle control: cyclins and cyclin-‐dependent kinases (Cdks) • The ac
LE 12-‐14 Proteins within the cell control the cell cycle Signals affecting critical checkpoints determine whether the cell will divide (cyclins, kinases)
G1 checkpoint
G1
S Control system M
M checkpoint G2 checkpoint
G2
Control of the Cell Cycle At G1/S checkpoint: -‐ G1 cyclins accumulate -‐ G1 cyclins bind with Cdc2 to create the ac
32
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Degraded cyclin Cyclin is degraded
G2 checkpoint
MPF
Cdk
in accumula2on Cycl
Cdk
Cyclin
Molecular mechanisms that help regulate the cell cycle
Rela2ve concentra2on
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M
G1
S
G2
M
G1 S
G2
M
MPF ac2vity Cyclin
Time Fluctua2on of MPF ac2vity and cyclin concentra2on during the cell cycle
External Factors that can Influence Cell Division
1. Chemical factors-
a. Lack of nutrients inhibit cell division b. Presence of specific growth factors are needed for cell division – Platelet-derived Growth Factor (PDGF) is required for division of fibroblasts used in healing – Receptors on plasma membrane bind PDGF and trigger pathway to signal cell division
2. Physical factors-
a. Density-dependent inhibition
• Cell division limited by quantities of nutrients and growth regulators
b. Anchorage-dependent inhibition • Cells must attach to substratum (surface) • Anchorage is signaled to cell-cycle control system by linkage between membrane proteins and elements of cytoskeleton
External Regulators • External regulators -‐ Proteins that respond to events outside the cell are called external regulators. • External regulators direct cells to speed up or slow down the cell cycle. • Growth factors are among the most important external regulators, which tell cells to speed up division. When is this important? • Molecules found on the surfaces of neighboring cells omen have an opposite effect, causing cells to slow down or stop their cell cycles.
External Signals
1. Growth factors stimulate cell division
Density-dependent inhibition of cell division
Cells anchor to dish surface and divide (anchorage dependence). When cells have formed a complete single layer, they stop dividing (density-‐dependent inhibi2on).
If some cells are scraped away, the remaining cells divide to fill the gap and then stop (density-‐dependent inhibi2on).
Normal mammalian cells
25 µm
• Mitosis occurs only if: – the cell is large enough – and the DNA is undamaged • If the DNA is damaged, the cell commits suicide – so it doesn’t pass on bad DNA
How DNA damage arrests the cell cycle?
Control of Cell Cycle What happens when checkpoints fail? Cancer can occur Cancer is the uncontrolled growth of cells.
Cancer Cells have Escaped Cell-cycle Control Cancer cells do not respond normally to the body’s control mechanisms and divide excessively 1. Density-independent—make their own growth factors and continue to divide uncontrolled (“immortal”) 2. Anchorage-independent
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Cells anchor to dish surface and divide (anchorage dependence).
When cells have formed a complete single layer, they stop dividing (density-‐dependent inhibi2on).
If some cells are scraped away, the remaining cells divide to fill the gap and then stop (density-‐dependent inhibi2on).
Normal mammalian cells
25 µm
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Cancer cells do not exhibit anchorage dependence or density-‐dependent inhibi2on.
25 µm Cancer cells
Loss of Cell Cycle Controls in Cancer Cells • Cancer cells do not respond normally to the body’s control mechanisms • Cancer cells form tumors, masses of abnormal cells within otherwise normal
Abnormal cells that escape cell-cycle control are products of mutated or transformed normal cells
1. May proliferate to form a tumor—an unregulated growing mass of cells within normal tissue • Benign tumor—if cells remain at the original site • Malignant tumor—if mass impairs normal function of one or more organs of the body » Excessive proliferation » Cells with unusual number of chromosomes » Aberrant metabolism » Detaches and migrates through body (metastasis)
Growth control in a normal cell Signaling cell
Growth factor = Growth factor binds to receptor Receptor sets off a signal cascade to nucleus
target cell
Nucleus
target cell enters S-phase and divides, eventually repairing wound
Several ways to get faulty growth control in a cancer cell 2. Mutant receptor might turn on even without binding growth factor
1. Cell might produce its own growth factor
3. Signal cascade might occur even without trigger from receptor
Breast cancer cell
Mammogram: normal (left) and cancerous (right)
What causes Cancer? • Cancer is caused by alterations or mutations in the genetic code • Can be induced in somatic cells by:
– Carcinogenic chemicals – Radiation – Some viruses • Heredity - 5% 53
• What is the molecular basis of cancer? • Cancer is a gene
55
What are the genes responsible for tumorigenic cell growth? Normal Proto-oncogenes
+
Tumor suppressor genes
-
Cell growth and proliferation
Cancer Mutated or activated oncogenes Loss or mutation of Tumor suppressor genes
++
Malignant transformation
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The Cell Cycle and Cancer • Characteristics of Cancer Cells • Cancer cells lack differentiation. • Cancer cells have abnormal nuclei. • Cancer cells form tumors. • Cancer cells undergo metastasis and angiogenesis.
Cancer cells lack differentiation • Unlike normal cells that differentiate into muscle or nerves cells, cancer cells have an abnormal form and are nonspecialized. • Normal cells enter the cell cycle only about 50 times; cancer cells are immortal in that they can enter the cell cycle repeatedly.
Cancer cells have abnormal nuclei • The nuclei may be enlarged and may have an abnormal number of chromosomes. • The chromosomes have mutated; some chromosomes may be duplicated or deleted. • Gene amplification, extra copies of genes, is more frequent in cancerous cells. • Whereas ordinary cells with DNA damage undergo apoptosis, cancer cells do not.
Cancer cells form tumors • Normal cells are anchored and stop dividing when in contact with other cells; i.e., they exhibit contact inhibition. • Cancer cells invade and destroy normal tissue and their growth is not inhibited. • Cancer cells pile on top of each other to form a tumor.
Cancer cells undergo metastasis and angiogenesis • A benign tumor is encapsulated and does not invade adjacent tissue. • Cancer in situ is a tumor in its place of origin but is not encapsulated—it will invade surrounding tissues. • Many types of cancer can undergo metastasis, in which new tumors form which are distant from the primary tumor. • Angiogenesis, the formation of new blood vessels, is required to bring nutrients and oxygen to the tumor. • A cancer patient’s prognosis depends on whether the tumor has invaded surrounding tissue, whether there is lymph node involvement, and whether there are metastatic tumors elsewhere in the body.
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Lymph vessel
Tumor
Blood vessel
Glandular 2ssue Cancer cell A tumor grows from a single cancer cell.
Cancer cells invade neighboring 2ssue.
Cancer cells spread through lymph and blood vessels to other parts of the body.
Metasta2c tumor A small percentage of cancer cells may survive and establish a new tumor in another part of the body.
Cancer treatment: Attack Actively Dividing Cells •
Three treatments for cancer: 1. Surgery 2. Radiation 3. Phase-specific chemotherapies
Phase-specific Chemotherapies 1. Prevent cells from entering the S-phase
2. Block the S phase
3. Block or stop mitosis
Phase Specificity of Cytotoxic Drugs Phase of cell cyle
Effective agents
G1
Steroids, asparaginase
S phase
Antimetabolites
G2
Bleomycin, etoposide
Mitosis
Vinca alkaloids, taxanes
Phase non-specific
Alkylating agents, nitrosoureas, antibiotics, procarbazine, dacarbazine, platinums
But chemotherapy can’t discriminate between cancer cells and normal cells…. • May affect all rapidly dividing cells • Which cells divide rapidly?
• So.... what would be the side effects?
Chemotherapy Side Effects • Chemotherapy targets cells which are dividing rapidly. • Chemotherapy cannot dis
The End
