Lecture 18: Cell Regulation and Cancer Bio Sci 93

Checkpoints

Critical control points in the cell cycle where stop and go signals regulate the cycle.

The three main checkpoints

The G1 checkpoint, the G2 checkpoint, and the M checkpoint. They are monitored by the cell cycle control system.

G1 checkpoint

Without a go-ahead signal, the cell exits the cycle and enters G0. With a go-ahead signal, the cell continues through the cell cycle.

G0 phase

Nondividing state a cell enters when it does not receive the go-ahead signal at the G1 checkpoint.

G2 checkpoint

Control point regulated by MPF. The cell passes it when there is sufficient MPF activity, and then enters mitosis.

M checkpoint

Spindle checkpoint at prometaphase and metaphase. The cell receives a stop signal when any chromosomes are not attached, and a go-ahead signal (to proceed to anaphase) when all chromosomes are attached.

Protein kinase

Enzyme that gives the go-ahead signals at the G1 and G2 checkpoints.

Cyclin-dependent kinase (Cdk)

Protein kinase that is only active when attached to a cyclin. That is why these kinases are called cyclin-dependent kinases.

Cyclin

Regulatory protein whose concentration fluctuates during the cell cycle. A Cdk must bind a cyclin to be active.

MPF (maturation-promoting factor)

Cyclin + Cdk. Its activity fluctuates with cyclin concentration. MPF regulates the G2 checkpoint and promotes mitosis.

How MPF is regulated

Cyclin begins to be synthesized and builds up. Once there is sufficient MPF (Cdk bound to cyclin), the cell passes the G2 checkpoint and MPF promotes mitosis. Cyclin is then degraded and the Cdk becomes inactive again.

G1/S checkpoint mechanism

CDK4/6 and cyclin D signaling is key. It removes inhibition of gene expression, so the genes necessary for DNA replication are expressed.

Growth factor

Extracellular signal protein that stimulates cells to divide. Provides a go-ahead signal for the cell cycle.

Platelet-derived growth factor (PDGF)

Growth factor that stimulates cell division. In culture, cells fail to divide without PDGF and proliferate when it is added.

Cancer

What happens when cell cycle regulation fails. Cancer cells divide uncontrollably.

Anchorage dependence

Normal cells must be attached to a substrate (surface) in order to divide. Cancer cells lose this property.

Density-dependent inhibition

Normal cells stop dividing when they become crowded and touch neighboring cells. Cancer cells lose this property.

Hallmarks of cancer cells

Cancer cells lose anchorage dependence and density-dependent inhibition, so they keep dividing without normal restraints.

Tumor and metastasis

1) A tumor grows from a single cancer cell. 2) Cancer cells invade neighboring tissue. 3) Cancer cells spread through lymph and blood vessels to other parts of the body. 4) A small percentage of cancer cells may metastasize, forming a metastatic tumor in another part of the body.

Metastasis

Spread of cancer cells from the original tumor to other parts of the body via the lymph and blood vessels.

How a normal cell becomes a cancer cell

Through mutations that disrupt cell cycle regulation, such as converting a proto-oncogene into an oncogene or losing a tumor suppressor gene.

Proto-oncogene

Normal cellular gene corresponding to an oncogene. It has the potential to cause cancer but requires some alteration to become an oncogene. Codes for a protein that stimulates normal cell growth and division.

Oncogene

Gene found in viruses or as part of the normal genome that is involved in triggering cancerous characteristics.

Mutations convert a proto-oncogene to an oncogene

A mutation in a proto-oncogene can make its protein hyperactive or overproduced. Example: a hyperactive Ras protein constitutively activates the cell cycle.

Ras

Gene whose normal protein stimulates cell division. A hyperactive Ras protein constitutively activates the cell cycle, so cells keep dividing.

Tumor suppressor gene

Gene whose normal product inhibits cell division, in contrast to proto-oncogenes, which normally promote cell division. Prevents uncontrolled cell growth.

p53

Tumor suppressor gene product known as the "guardian of the genome." It acts as a brake on the cell cycle, and losing it takes the brakes off cell cycle inhibition.

Proto-oncogenes vs. tumor suppressors

Proto-oncogenes are like the gas pedal (they stimulate the cycle when activated or overactive as oncogenes). Tumor suppressor genes are like the brakes (they inhibit the cycle, and cancer can result when they are lost).

Best way to remove a cell's brakes

Lose a tumor suppressor gene, which removes inhibitory signaling of the cell cycle. (Expressing an oncogene overstimulates the cycle instead.)

Multistep model of cancer

Colorectal cancer develops through the accumulation of multiple mutations, including both oncogene activation and tumor suppressor loss. If the multistep model is true, the incidence of cancer increases greatly with age.

Cancer and body size reasoning

Cancer develops through the accumulation of mutations. An organism with a larger body has more cells and so more chances to accumulate mutations, so you would expect cancer probability to rise with body size.

Peto's paradox

Across species there appears to be no correlation between body size and cancer rate, even though larger animals have more cells.

Why elephants have low cancer risk

Elephants are large but have much lower cancer risk than humans. A leading explanation, which the slide leaves blank, is that elephants have extra copies of the p53 tumor suppressor gene.

Cell cycle inhibitor as cancer therapy

A drug like "93stop" that stops cell cycle progression at a specific stage may be effective against cancer cells that have lost regulation and are dividing uncontrollably. Results from the histograms support the hypothesis.

Reading the 93stop histograms

Fluorescence per cell indicates DNA content. Peak A is cells at the end of G1, B is the end of S, and C is the end of G2. Compare the treated histogram with the control: the phase where cells pile up is the stage where the inhibitor stops the cell cycle.

Why an inhibitor stops the cycle at a specific stage

The cell cycle is controlled by checkpoints. An inhibitor of a stage-specific regulator (for example, a Cdk/cyclin complex) blocks progress at that checkpoint.