Transcript Regulation of the Cell Cycle / Cancer

Regulating the Cell Cycle
Chapter 12.3
Cellular Biology
What you need to know!
• The cell cycle is regulated by a molecular
control system
• Cancer results from genetic changes that
affect cell cycle control.
Signals Influencing Cell Cycle
• Can be internal (current situation of cell)
– Start and stop signals
• External (hormones, space)
– start and stop signals
Internal Signals
Stop Signals:
• Cell too small, not enough nutrients
available
• Incomplete DNA synthesis
• Incomplete kinetochore attachment
Start Signals:
• High levels of hormone Cyclin
• Active form of MPF (mitosis promoting
factor) kinase – MPF concentration is
stable but exists in inactive and active form
• Completed DNA replication
• Successful attachment of all sister
chromatids to kinetochore spindle fibers
External Signals
Stop signals:
• No room or surrounding space to grow (in
vivo and vitro)
• No anchorage in Petri dish (in vitro)
Start signals:
• Growth hormones
– PDGF – platelet derived growth factor
– GH – various growth hormones
• Example: HGH = human growth hormone
I. Cell-Cycle Checkpoints
• Checkpoints at crucial places where cell
division comes to a halt:
• G1 Restriction point: will cell enter G0 or
S?
• S checkpoint: is all DNA duplicated?
• G2 checkpoint: is everything ready for
mitosis?
• M (metaphase) checkpoint: are all sister
chromatids ready for separation?
Each checkpoint needs to be overridden by
the specific go ahead signals for this phase
G1 Restriction Point
• Cell is fully mature
• Space is present
• Nutrients present
= Growth hormones will induce S-phase
OR
• Cell is not fully mature
• No space
• Limited nutrients
• No growth hormones
= cell will enter G0
S Checkpoint
• DNA is completely duplicated
• Rising levels of Cyclin
G2 Checkpoint
• Peak levels of cyclin
• Increased activation of MPF kinase leads
to nuclear envelope disintegration and
prophase
Metaphase Checkpoint
• Kinetochore spindle fibers successfully
attached to all kinetochore motors, which
sends signals that disintegrate protein
clamps between sister chromatids
• Cyclin is degraded
• MPF kinase is deactivated
Cell-Cycle Control in Cancer
Cells
•
•
a.
b.
c.
d.
Cancer cells have numerous mutations
(cumulative mutations increase with age)
in the genes that code for restriction point
protein machinery
They escape the normal cell cycle control
mechanisms
No density dependent inhibition (in vivo
and vitro)
No anchorage dependence (in vitro)
No dependence on growth factors
Cancer cells are immortal (no cell cycle
limit)
Biology of Cancer
•
If cells become abnormal they are located
by the immune system and destroyed
• If they evade recognition they will start
forming tumors
Benign tumors
• Cells stay at original location
• Slow proliferation
Malignant Tumors
• Invade other locations: metastasis  cells
breaking off the tumor get carried by the
blood stream and get stuck in other
capillary beds (lungs, liver, kidneys) or
cycle through the lymphatic system and
get stuck in the lymph nodes
• Uncontrolled proliferation: constant cell
cycling/mitosis
– chemotherapy drugs attack all cells in cell cycle
by blocking the formation of spindle fibers
• Cancer cells send signals to the body to
provide angiogenesis = growth of blood
vessels into growing tumors
– anti angiogenesis drugs are used as treatment
Malignant Tumors
• Can differ in: # of chromosomes,
metabolic rate, abnormal cell surfaces,
and large nuclei
• Names include: carcinoma, sarcoma,
lymphoma, etc.
• There are 4 levels of malignancy for
cancer cells indicating how
aggressive/mutated the cell is with level 1
being the least and level 4 being the most
aggressive type of cancer
• Viruses can cause cancer (HPV & cervical
cancer)
• There is a genetic predisposition for
cancer (it’s hereditary)
Cancer = Hereditary
• Proto-oncogenes help regulate the cell
cycle and facilitate cell-cell communication
– When to divide
– Cell recognition (signal transduction)
• Mutated proto-oncogenes are called
oncogenes are tumor-promoting
• Oncogenes are found in most cancer cells
found in malignant tumors
• Tumor-suppressing genes help keep
cancers from developing in two ways:
1. Preventing cell division until DNA is repaired
2. Cell suicide
• All genes are inherited