Download The Cell Cycle

Control of the
Cell Cycle
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Cell Cycle Control
• Cell cycle controlled by internal and external
signals
–External signals
• Growth factors
• Received at the plasma membrane
• Cause completion of cell cycle
–Internal signals
• Family of proteins called cyclins
• Increase and decrease as cell cycle continues
• Without them cycle stops at G1, M or G2
• Allows time for any damage to be repaired
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The Cell Cycle
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Apoptosis
• Often defined as programmed cell death
• Mitosis and apoptosis are opposing forces
–Mitosis increases cell number
–Apoptosis decreases cell number
• Cells harbor apoptosis enzymes (caspases)
–Ordinarily held in check by inhibitors
–Can be unleashed by internal or external signals
• Signal protein P53
–Stops cycle at G1 when DNA damaged
–Initiates DNA attempt at repair
• If successful, cycle continues to mitosis
• If not, apoptosis is initiated
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Apoptosis
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Evidence for cytoplasmic chemical signals
2nd cell begins mitosis too early
Mammalian cells in different phases
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Role of protein kinases
Kinases transfer phosphates to
other proteins from ATP and
bring about further effects
in cell cycle events
Activity of protein kinases
depends of fluctuating
levels of proteins called
cyclins during cell cycle; and
their attachment to cyclins;
kinase referred to as a
Cdk (cyclin-dependent kinase)
(Cdk)
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G2 checkpoint regulation
• MPF = M-phase promoting factor
(1st cyclin-Cdk complex
discovered); “threshold effect”
– Causes chromosome condensation;
– nuclear envelope to fragment
– Brings about switching itself “off”
by promoting a proteolytic process
which destroys MPF (noncyclin part
of molecule persists in cell until
cyclin is regenerated again)
• Proteolytic enzymes also degrade
proteins which hold sister
chromatids together; allows
anaphase to begin
• G1 occurs in similar fashion with
rise and fall of other cyclins
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accumulation
• M-phase checkpoint depends on molecular
signaling from kinetochores
– Chromosomes must be attached to spindle microtubules
before anaphase may proceed
• Unattached kinetochores trigger a signaling pathway which
keeps APC (anaphase-promoting-complex) inactive
• After all kinetochores become attached, APC becomes active
– Contains proteolytic enzymes which degrade cyclin
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External signaling factors
• Chemical factors
– Essential nutrients: cells won’t divide without them
– Growth factors usually necessary for tissue-cultured
mammalian cells to divide
• PDGF = platelet-derived growth factor stimulates cell
division in fibroblasts
– PDGF is used in the laboratory as well as being found in mammals
during wound-healing
• Other types of cells probably have different receptors for
different growth factors or combinations of growth factors
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• Physical factors
– Crowding of cells
(density-dependent
inhibition) causes
cells to stop
growing.
• Too densely
packed cells might
have insufficient
nutrients and
growth regulators
to support cell
division
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• Anchorage-dependence
– For cell division, many cells must adhere to a
substratum (bottom of culture dish, extracellular matrix,
etc.)
• Communicate anchorage to cell-cycle control mechanism via
membrane proteins and cytoskeletal elements attached to
those proteins
• Cancer cells don’t display either density-dependent
inhibition or anchorage-dependent inhibition
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The Cell Cycle and Cancer
• Abnormal growth of cells is called a neoplasm
–Benign neoplasms are not cancerous
• Encapsulated
• Do not invade neighboring tissue or spread
–Malignant neoplasms are cancerous
•
•
•
•
Not encapsulated
Readily invade neighboring tissues
May also detach and lodge in distant places – metastasis
Results from mutation of genes regulating the cell cycle
• Carcinogenesis – development of cancer
–Tends to be gradual
–May be years before cell is obviously cancerous
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Cancer cells out of cell cycle loop
• Don’t stop growing or dividing when growth
factors are depleted
– May make own growth factors
• Are invasive
– Don’t demonstrate anchorage-dependence inhibition
• Are immortal
– Most cells’ “internal clocks” allow 20-50 cell divisions
before they stop; cancer cells keep on going
• Cancer cells that do stop dividing, do so at random
places in cell cycle -- not at checkpoints
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What about our immune system?
• Cells which escape normal cell cycle controls are
products of mutated or transformed cells
• Immune system normally recognizes and destroys
transformed cells which have converted from
normal cells
– When cancer cells escape destruction they may
proliferate into a tumor within normal tissue
• If cells remain in this isolated located the mass is a benign
tumor and can be surgically removed
• A malignant tumor becomes invasive and impairs normal
function of one or more body organs; at this time patient is
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said to have cancer
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Malignant tumors
• Anomalous (not normal) cell cycle; excessive
proliferation
• May contain unusual numbers of chromosomes
• May have aberrant metabolism
• Has lost attachments to neighboring cells and ECM
-- usually caused by abnormal cell surface changes.
• May become invasive into other tissues/organs -metastasis
– Metastasis treated with radiation and chemotherapy
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Characteristics of Cancer Cells
• Lack differentiation
• Have abnormal nuclei
• Form tumors
–Mitosis controlled by contact with neighboring cells –
contact inhibition
–Cancer cells have lost contact inhibition
• Undergo metastasis
–Original tumor easily fragments
–New tumors appear in other organs
• Undergo angiogenesis
–Formation of new blood2011-12
vessels
Cancer Cells Versus Normal Cells
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Cancer Cells
Origins of Cancer: Oncogenes
• Mutations in DNA repair mechanisms
• Oncogenes
–Proto-oncogenes promote the cell cycle in various ways
–Tumor suppressor genes inhibit the cell cycle in various
ways
–Both normally regulated in coordination with organism’s
growth plan
–If either mutates, may lose control and become oncogene
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Origins of Cancer: Telomerase
• Chromosomes normally have special material at
each end called telomeres (end parts)
• These get shorter each cell division
• When they get very short
–The cell will no longer divide
–Almost like running out of division tickets
• Telomerase is an enzyme that adds telomeres
• Mutations in telomerase gene:
–Keeps adding new telomeres
–Allow cancer cells to continually divide
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–Like counterfeit tickets
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Causes of Cancer
End
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