Cancer and the Cell Cycle

Outline of the lecture

What is cancer? Review of the cell cycle and regulation of cell

growth Which types of genes when mutated can cancer? Roles for screening for mutations in specific genes Tumor suppressor p53 Have you figured it out?

Overview of Cancer

Cancer: Abnormal proliferation of cells forming cell masses known as tumors.

Benign Malignant

Tumors

Slow growth rate Fast growth rate

Malignant Tumors

Malignant tumor cells have theability to travel through thecorporal fluids settling on othertissues.

This process is known as metastasis.

From a single cell new tumors can arise

According to the American Cancer Society

25 % of deaths in U.S. are caused by cancer.

~ 564,630 Americans are expected to die ofcancers in 2006.

American Cancer Society (ACS): www:cancer.org

What is cancer?

Cancer = uncontrolled proliferation of cells within the body tumor.

Tumor = clone of cells resulting from series of sequential genetic mutations loss of growth control.

Cancer is also known as malignancy. Development of cancer = oncogenesis Study or treatment of cancer = oncology

Cancer is a multi-step process.

This process continues, with each successive mutation leading to a faster rate of cell division, slower rate of cell death, and eventually loss of cell adhesion.

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Non-dividing cells

Review of the Eukaryotic Cell Cycle

The cell cycle The cell cycle has four phases:

M, during which the cell divides (undergoes mitosis);

G1, during which the cell grows larger; S , during which DNA synthesis occurs; G2, during which the cell continues to grow and

prepare for mitosis.

The cell cycle- regulation at several points

G1 Restriction Point time when the decision is made whether to

continue the cycle or to to exit the cycle in a nondividing state called G0.

Once the cell passes the restriction point in G1, the cycle will continue until it is arrested at one of several later checkpoints in response to some problem that needs to be corrected.

The cell cycle- regulation at several points (cont’d.) Late G1 and late G2 checkpoints

If DNA damage has occurred, these checkpoints allow time for the damaged DNA to be repaired before the cycle resumes.

Late G2 checkpoint also responds to the presence of unreplicated DNA and prevents mitosis from occurring until all of the DNA has been copied.

In the event that a cell enters an S phase with damaged DNA that can’t be repaired, apoptosis may be triggered to prevent the mutant cell from reproducing itself.

The cell cycle- regulation at several points (cont’d.)

Late M phase checkpoint Halts the cell cycle until all of the

chromosomes are properly aligned.

What is G0 ? Cells in G0 may differentiate and assume

specialized functions. A cell can remain in G0 indefinitely, or it may

re-enter the cell cycle in response to signals from a variety of growth factors.

Seven levels of regulation of cell growth

An unrepaired mutation in a gene for a DNA-repair protein, a cell-cycle control protein, or an anti-apoptosis protein can increase the likelihood of a cancer developing.

An Example of Cell Cycle Regulation by a Serum Growth Factor Cyclin D is made following the

binding of the serum growth factor to its receptor and the ensuing cascade of phosphorylations.

An Example of Cell Cycle Regulation by a Serum Growth Factor

Where and what kinds of mutations would lead to permanent expression of Cyclin D?

Phosphorylation of Rb is Regulated in turn by Cyclin D

Genes whose products move the cell through S phase.

Note multiple examples of cell cycle regulation by tumor suppressors (white circles)

The Cell Cycle Cyclins, CDKs, and CDKIs

Cyclins and Cyclin Dependent Kinases (CDKs) interact to move the cell cycle forward.Cyclins, and Cdks act together as a dimer,

functioning as the regulatory and catalytic subunits, respectively.

Cyclins are degraded at the end of their functional period, thus inactivating their Cdk partner in the dimer.

The assembly of the dimers is regulated by other proteins.

The Cell Cycle

Cyclins, CDKs, and CDKIs Cyclins, CDKs, and cyclin dependent kinase

inhibitors, (CDKIs) interact to block phases of the cycle.

Examples of Cell Cycle Regulation by a Serum Growth Factor and by Tumor Suppressors

Cyclin D associates with either Cdk4 or Cdk6. P16 may block the assembly. After assembly the Cdk becomes phosphorylated. This may be blocked by either p21 or p27 The target of the active dimer is Rb1 which is bound to a

transcription factor called E2F. The Rb1/E2F dimer blocks transcription of genes needed

to enter the S phase. Phosphorylation of Rb results in its dissociation from E2F. This results in activation of S phase genes.

In addition to its ability to block the association of cyclin D with a Cdk, P16 can also directly block the phosphorylation of Rb.

Examples of Cell Cycle Regulation by Tumor Suppressors

P16, p21, and p27 are regulated by p53 (more on this later) which blocks the cell cycle in the G1 phase if there is DNA damage.

P53, Rb1, p21, p16, and p27 are called tumor supressors because their normal function is to prevent the growth of cells with damaged DNA.

An Example of Cell Cycle Regulation by Tumor Suppressors

P53 also responds to unrepaired DNA damage by triggering apoptosis (programmed cell death) of the injured cell. P53 interacts with Bax, which, in turn activates

special enzymes called caspases. Bax is member of the Bcl-2 family of proteins, but

unlike Bcl-2, which prevents apoptosis, Bax activates apoptosis.

Caspases initiate a protease cascade that results in digestion of the DNA.

This ultimately leads to cell death.

Apoptosis – in response to irreparable DNA damage

Bax

Note the role of tumor suppressor p53.

Which types of genes when mutated can cancer?

Oncogenes = genes whose products turn DNA synthesis ON Tumor suppressors/anti-oncogenes = genes whose products

turn DNA synthesis OFF Genes whose products contribute to genomic stability, (e.g.)

repair DNA, limit synthesis to doubling the DNA content make sure DNA is completely doubled

Genes whose products contribute to cell longevity In each case, ask yourself: would the mutation contributing

to the development of cancer be an activating mutation or an inactivating mutation?

Which types of genes when mutated can cancer? Oncogenes (turn DNA synthesis ON)

In progression towards cancer, a gene for a protein that normally stimulates DNA synthesis (proto-oncogene) is either consitutively expressed at high levels or

• Change in the regulation of the gene mutated such that protein product is constitutively active, i.e., can

not be inactivated• Change in the protein for which the gene codes

Note: be sure you can distinguish between these two types of changes – in the regulation, or in the protein product itself.

Mutations in classes I-IV from Slide # 15 generally give rise to dominantly active oncogenes.

Examples: see next slide.

Oncogenes

Which types of genes when mutated can cancer? Tumor suppressors/anti-oncogenes (turn DNA

synthesis OFF) In the progression towards cancer, a gene for a

protein that normally inhibits DNA synthesis is either permanently inactivated or mutated such that the protein product is inactive

Mutations in Class VI, cell-cycle control proteins, from Slide #15.

Examples: APC inhibits Wnt gene product from activating myc Rb1 inhibits activation of transcription of DNA synthesis

genes

Which types of genes when mutated can cancer?

Contributors to genomic stability Some tumor suppressors turn DNA synthesis

off when DNA is damaged. The progression toward cancer occurs when a

gene for a protein which contributes to DNA repair ispermanently inactivated ormutated such that protein product is inactive

Which types of genes when mutated can cancer?

Contributors to genomic stability Mutations in repair genes increase likelihood of

mutations in proto-oncogenes and tumor suppressors.

Examples:p53 gene product induces genes for DNA repairMDM2 gene product destabilizes p53MutS and MutL gene products repair UV or

chemically damaged DNA

Which types of genes when mutated can cancer?

Contributors to cell longevity (anti-apoptosis genes) Progression toward cancer can occur when an anti-

apoptosis gene is constitutively expressed or mutated such that protein product is constitutively

active Allows survival of cells with oncogenic mutations Example: Bcl2

Roles for screening for mutations in specific genes

To determine Type of cancer Familial predispositions Progression of the cancer