Oncogenes and tumour suppressor genes

Introduction

cell division process is dependent on a tightly controlled sequence of events.

dependent on the proper levels of transcription and translation of certain genes.

When this process does not occur properly, unregulated cell growth may be the end result.

Mutation

Introduction

Of the 30,000 or so genes that are currently thought to exist in the human genome, there is a small subset that seems to be particularly important in the prevention, development, and progression of cancer.

These genes have been found to be either malfunctioning or non-functioning in many different kinds of cancer.

The genes have been categorized into two broad categories, depending on their normal functions in the cell.

Genes whose protein products stimulate or enhance the division and viability of cells. This first category also includes genes that contribute to tumour growth by inhibiting cell death.

Genes whose protein products can directly or indirectly prevent cell division or lead to cell death.

The normal versions of genes in the first group (whose protein products stimulate or enhance the division

and viability of cells )are called proto-oncogenes. The mutated or otherwise damaged

versions of these genes are called oncogenes.

The genes in the second group (whose protein products can directly or indirectly prevent cell division or lead to cell

death) are called tumour suppressors.

tumour suppressors function in many key cellular processes including the regulation of transcription, DNA repair and cell:cell communication.

The loss of function of these genes leads to abnormal cellular behavior.

DNA tumour viruses

Important role in current understanding of neoplasia.

Viruses produce proteins - target key cellular regulatory proteinsRb, p53

tumour Suppressor Genes

Some genes suppress tumour formation. Their protein product inhibits mitosis. When mutated, the mutant allele behaves as a

recessive; that is, as long as the cell contains one normal allele, tumour suppression continues.

(Oncogenes, by contrast, behave as dominants; one mutant, or overly-active, allele can predispose the cell to tumour formation).

Example 1: RB - the retinoblastoma gene

Retinoblastoma is a cancerous tumour of the retina. It occurs in two forms: Familial retinoblastoma

Multiple tumours in the retinas of both eyes occurring in the first weeks of infancy.

Mechanism. The Rb protein prevents cells from entering S phase of the cell cycle. It does this by binding to a transcription factor called E2F.

Example 2: p53

The product of the tumour suppressor gene p53 is a protein of 53 kilodaltons (hence the name).

The p53 protein prevents a cell from completing the cell cycle if its DNA is damaged or the cell has suffered other types of damage.

When the damage is minor, p53 halts the cell cycle — hence cell division — until the damage is repaired. the damage is major and cannot be repaired, p53 triggers the cell to commit suicide by apoptosis.

These functions make p53 a key player in protecting us against cancer; that is, an important tumour suppressor gene.

More than half of all human cancers do, in fact, harbour p53 mutations and have no functioning p53 protein.

Loss Of Heterozygosity (LOH)

Because tumour suppressor genes are recessive, cells that contain one normal and one mutated gene — that is, are heterozygous — still behave normally.

However, there are several mechanisms which can cause a cell to lose its normal gene and thus be predisposed to develop into a tumour. These may result in a "loss of heterozygosity" or "LOH".

Mechanisms of LOH:1. Deletion of

the normal allele; the chromosome arm containing the normal allele; the entire chromosome containing the normal allele (resulting in aneuploidy).

2. Loss of the chromosome containing the normal allele followed by duplication of the chromosome containing the mutated allele.

3. Mitotic recombination. The study of tumour suppressor genes revealed (for the first time) that crossing over — with genetic recombination — occasionally occurs in mitosis (as it always does in meiosis).

In #2 and #3, the resulting cell now carries two copies of the "bad" gene. This is called "reduction to homozygosity".

tumour suppressor genes = anti-oncogenes

Genes like RB and p53 are also called anti-oncogenes. They were first given this name because they reverse, at least in cell culture, the action of known oncogenes.

Human Papillomavirus (HPV)

Once inside the cells of their host, human papilloma viruses synthesise

a protein designated E7 and another designated E6.

Human Papillomavirus

The E7 protein of one of these binds to the Rb protein preventing it from binding to the host transcription factor E2F. Result: E2F is now free to bind to the promoters of genes (like c-myc) that cause the cell to enter the cell cycle . Thus this version of E7 is an oncogene product.

The E6 protein of human papilloma virus implicated in cervical cancer binds the p53 protein targeting it for destruction by proteasomes and thus removing the block on the host cell's entering the cell cycle.

Oncogenes

Genes associated with the stimulation of cell division.

Cancers result from only one mutant allele of gene.

Oncogenes

1. Growth Factors or Receptors for Growth Factors

PDGF Platelet Derived Growth Factor (brain and breast cancer) erb-B receptor for epidermal growth factor (brain and breast cancer) erb-B2 receptor for growth factor (breast, salivary, and ovarian cancers) RET growth factor receptor (thyroid cancer)

Oncogenes

3. Transcription Factors that Activate Growth Promoting Genes

c-myc activates transcription of growth stimulation genes (leukemia, breast, stomach, and lung cancer) N-myc (nerve and brain cancer) L-myc (lung cancer) c-jun and c-fos function as transcription factors

MYC

The myc protein acts as a transcription factor and it controls the expression of several genes.

Mutations in the myc gene have been found in many different cancers, including Burkitt's lymphoma, B-cell leukemia, and lung cancer.

The myc family of oncogenes may become activated by gene rearrangement or amplification.

Gene rearrangements involve the breakage and re-sealing of chromosomes.

This process can involve large amounts of DNA and can affect many genes.

The movement of a gene or group of genes to a different location within the same chromosome or to a different chromosome often leads to altered gene expression and cell function.