When it comes to cancer and how things can go wrong in the cell cycle, three different genes are very important:

• An oncogene is a proto-oncogene that has been mutated. Proto-oncogenes stimulate the cell to grow, divide and move through each cell cycle checkpoint to be inspected. If a proto-oncocogene mutates, it becomes an oncogene and no longer stops at cell checkpoints to insure it is normal.


• Tumor-suppressor genes act to stop cell growth


• DNA repair genes fix errors

Oncogenes: The bad guys, turn abnormal cell growth on (go/gas pedal)

An oncogene is a proto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth- i.e., cancer. This is like pushing down on the gas pedal - you now have a gene that is telling the cell, "go, go, go; don't pay attention to the checkpoint and stop". Not all genes can mutate and form oncogenes. Only "proto-oncogenes" can mutate to form an oncogene. There are about 70 proto-oncogenes in our DNA.

Image courtesy of the National Cancer Institute

Oncogenes are mutated genes whose PRESENCE can stimulate the development of cancer.

When oncogenes arise in normal cells, they can contribute to the development of cancer by telling cells to make proteins that stimulate excessive cell growth and division.

Oncogenes are "gain of function" genes. They gain the ability to drive non-stop growth. In spite of their dominant activities, a single mutated oncogene usually isn't enough to cause cancer all by itself because tumor-suppressor genes are acting to put the brakes on to keep cell growth from getting out of control.

Oncogenes aren't usually involved in inherited forms of cancer because most occur as somatic mutations and can't be passed from parent to child.

A few important oncogenes:

• HER-2/neu
  • HER-2/neu encodes for a cell surface receptor that can stimulate cell division. The HER-2/neu gene is amplified in up to 30% of human breast cancers.
  
  
• RAS
  • The Ras gene products are involved in kinase signaling pathways that ultimately control transcription of genes, regulating cell growth and differentiation.
  
  
• MYC
  • The Myc protein is a transcription factor and controls expression of several genes.
  
  
• SRC
  • Src was the first oncogene ever discovered. The Src protein is a tyrosine kinase, which regulates cell activity.
  
  
• hTERT
  • hTERT codes for an enzyme (telomerase) that maintains chromosome ends.

 

Other Bad Guys:

While the prime suspects for cancer-linked mutations are the oncogenes, mutated tumor suppressor genes, and faulty DNA repair genes, the mutations listed below also do damage.

Mutations also are seen in genes that:

• Activate and deactivate carcinogens


• Govern the cell cyc


• Control cell senescence (or "aging")


• Control cell suicide (apoptosis)


• Control cell signaling


• Control cell differentiation


• Enable cancer to invade and metastasize to other parts of the body.

Tumor-Suppressor Genes: The good guys, turn cell growth off (stop/brake pedal)

Tumor suppressor genes in normal cells act as braking signals during phase G1 of the cell cycle, to stop or slow the cell cycle before S phase. If tumor-suppressor genes are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth, i.e. cancer.

		Tumor suppressorgenes are normal genes whose ABSENCE can lead to cancer.
Image courtesy of the National Cancer Institute

Mutations in tumor-suppressor genes cause loss-of-function. Loss-of-function mutations generally only show up when both copies of the gene are mutated. In other words, if a pair of tumor suppressor genes are lost or mutated, their functional absence might allow cancer to develop.

Individuals who inherit an increased risk of developing cancer often are born with one defective copy of a tumor suppressor gene.

Because genes come in pairs (one inherited from each parent), an inherited defect in one copy will not lead to cancer because the other normal copy is still functional. But if the second copy undergoes mutation, the person then may develop cancer because there no longer is any functional copy of the gene.

A few important tumor-suppressor genes:

• p53: a transcription factor that regulates cell division and cell death.


• Rb: alters the activity of transcription factors and therefore controls cell division.


• APC: controls the availability of a transcription factor.

 

More Good Guys - DNA Repair Genes: Correct errors

DNA repair genes code for proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to cell division.

DNA repair genes are active throughout the cell cycle, particularly during G2 after DNA replication and before the chromosomes divide.

Mutations in DNA repair genes can lead to a failure in repair, which in turn allows subsequent mutations to accumulate. Certain forms of hereditary colon cancer involve defects in DNA repair.

Image courtesy of Dr Harold Brenner

If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in cancer.

A few important DNA repair genes:

• BRCA1 and BRCA2

 

CISN Summary: Oncogenes, Tumor-Suppressor Genes and
DNA Repair Genes

This is a lot of information to understand, so we have a short summary for those who just want to remember the basics.

For those that want to know more - reread the section, print the entire section, maybe even take notes to help you memorize the information, if that is important to you. It always helps to have study buddies, take breaks and remember you don't have to memorize all the material. It is here to help you when you need to understand something specific.

	Most cancer cells acquire a number of common abnormalities The causes and sequence of the abnormalities varies Effective therapies reverse at least several of the abnormalities Mutated genes: see table

Name of Gene	This Mutation Causes	Examples
Oncogene	Uncontrolled growth: step on the gas	Her2-neu, Ras, Myc, Src, Htert
Tumor Suppressor	Uncontrolled growth: remove the brake	P53, Rb, APC
DNA Repair	No longer able to correct cell division mistakes	BRCA1 and BRCA2