Regulation of the Cell Cycle / Cancer

Chapter 12

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 attachmentStart 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

• 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

a. No density dependent inhibition (in vivo and vitro)

b. No anchorage dependence (in vitro)

c. No dependence on growth factors

d. 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• There is a genetic predisposition for

cancer (it’s hereditary)