Tuesday, October 6, 2009

tumour supressor genes-cancerbiology-unit-8-btechbiotechnology

Tumor suppressor genes prevent the uncontrolled growth of cells that may result in cancerous tumors.antioncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.A protective gene that normally limits the growth of tumors. When a tumor suppressor gene is mutated (altered), it may fail to keep a cancer from growing.

BRCA1, an example of tumor suppressor genes, was the first breast cancer gene to be identified; mutated forms of this gene are responsible for some cases of inherited breast cancer, especially those that occur in younger women.

Two-hit hypothesis

Unlike oncogenes, tumor suppressor genes generally follow the 'two-hit hypothesis', which implies that both alleles that code for a particular gene must be affected before an effect is manifested. This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. In other words, mutant tumor suppressors alleles are usually recessive whereas mutant oncogene alleles are typically dominant. The two-hit hypothesis was first proposed by A.G. Knudson for cases of retinoblastoma.[1] Knudson observed that the age of onset of retinoblastoma followed 2nd order kinetics, implying that two independent genetic events were necessary. He recognized that this was consistent with a recessive mutation involving a single gene, but requiring biallelic mutation. Oncogene mutations, in contrast, generally involve a single allele because they are gain of function mutations. There are notable exceptions to the 'two-hit' rule for tumor suppressors, such as certain mutations in the p53 gene product. p53 mutations can function as a 'dominant negative', meaning that a mutated p53 protein can prevent the function of normal protein from the un-mutated allele.[2] Other tumor-suppressor genes that are exceptions to the 'two-hit' rule are those which exhibit haploinsufficiency. An example of this is the p27Kip1 cell-cycle inhibitor, in which mutation of a single allele causes increased carcinogen susceptibility.

Functions of tumour supressor genes

Tumor-suppressor genes, or more precisely, the proteins for which they code, either have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes do both. The functions of tumor-suppressor proteins fall into several categories including the following:[4]

1. Repression of genes that are essential for the continuing of the cell cycle. If these genes are not expressed, the cell cycle will not continue, effectively inhibiting cell division.
2. Coupling the cell cycle to DNA damage. As long as there is damaged DNA in the cell, it should not divide. If the damage can be repaired, the cell cycle can continue.
3. If the damage cannot be repaired, the cell should initiate apoptosis (programmed cell death) to remove the threat it poses for the greater good of the organism.
4. Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of contact inhibition, and inhibit metastasis. These proteins are known as metastasis suppressors.

types of tumour supressor genes:

The first tumor-suppressor protein discovered was the Retinoblastoma protein (pRb) in human retinoblastoma; however, recent evidence has also implicated pRb as a tumor-survival factor.

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. This prevents E2F from binding to the promoters of such proto-oncogenes as c-myc and c-fos. Transcription of c-myc and c-fos is needed for mitosis so blocking the transcription factor needed to turn on these genes prevents cell division.

Another important tumor suppressor is the p53 tumor-suppressor protein encoded by the TP53 gene. Homozygous loss of p53 is found in 70% of colon cancers, 30–50% of breast cancers, and 50% of lung cancers. Mutated p53 is also involved in the pathophysiology of leukemias, lymphomas, sarcomas, and neurogenic tumors. Abnormalities of the p53 gene can be inherited in Li-Fraumeni syndrome (LFS), which increases the risk of developing various types of cancers.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.


* 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 tumor suppressor gene. More than half of all human cancers do, in fact, harbor p53 mutations and have no functioning p53 protein.

others include brca1, pten tumour genes
thus tumour genes play an important role in controm of cancer.. also called as anti metastasis agents

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