Recombinant DNA Technology Prof.(Dr.) Punam Jeswal Head M.Sc semester lll Botany Department

Oncogene Or Tumor Suppressor Gene

Oncogene - An oncogene is a agene that has the potential to cause cancer. In tumor cell, they are often mutated or expressed at high levels.

The term "oncogene" was coined in 1969 by National Cancer Institute scientists, George Todaro and Robert Heubner.

The first confirmed oncogene was discovered in 1970 and was termed src (pronounced sarc as in sarcoma). Src was in fact first discovered as an oncogene in a chicken retrovirus. Experiments performed by Dr. G. Steve Martin of the University of California, Berkeley demonstrated that the Src was indeed the oncogene of the virus. The first nucleotide sequence of v-src was sequenced in 1980 by A.P. Czemilofsky et al.

In 1976 Drs. Dominique Stehelin, J. Michael Bishop and Harold E. Varmus of the University of California, San Francisco demonstrated that oncogenes were activated proto-oncogenes, found in many organisms including humans. For this discovery, proving Todaro and Heubner's "oncogene theory", Bishop and Varmus were awarded the Nobel Prize in Physiology or Medicine in 1989.

A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. The resultant protein may be termed as oncoprotein. Proto- oncogenes code for protein that help to regulate cell growth and differentiation. Proto- oncogene are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. Upon activation, a proto-oncogene (or its products) become a tumor-inducing agent, an oncogene. Examples of proto-oncogene includes RAS, WNT, MYC, ERK, and TRK.

The MYC gene is implicated in Burkitt's Lymphoma, which starts when a chromosomal translocation moves an enhancer sequence within the vicinity of the MYC gene.

The MYC gene codes for widely used transcription factors. when the enhancer sequence is wrongly placed, these transcription factors are produced at much higher rates. Another example of an oncogene is the Ber-Abl gene found on the Philadelphia Chromosome, a pieces of genetic material seen in Chronic Myelogenous Leukemia caused by the translocation of pieces from chromosome 9 and 22. Ber-Abl codes for a receptor tyrosine kinase, which is constitutively active, leading to uncontrolled cell proliferation.

Most normal cells undergo a programmed from of death(apoptosis). Activated oncogene can cause those cells designated for apoptosis to survive and proliferate instead. Most oncogene require an additional step, such as mutation in another gene, or environmental factors, such as viral infection, to cause cancer. Since the 1970s, dozens of oncogene have been identified in human cancer. Many cancer drugs target the protein encoded by oncogenes.

The activation of oncogene involves genetic changes to cellular proto-oncogene. The consequence of these genetic alterations is to confer a growth advantage to the cell. Three genetic mechanisms activate oncogenes in human neoplasm :-

(1) Mutation. (2) Gene Amplification. (3) chromosome rearrangement.

These mechanism result in either an alteration of proto-oncogene structure or an increase in proto-oncogene expression. Because neoplasia is a multistep process, more than one of these mechanisms often contribute to the genesis of human tumors by altering a number of cancer-associated genes. Full expression of the neoplastic phenotype, including the capacity for metastasis, usually involves a combination of proto-oncogene activation and tumor suppressor gene loss or inactivation.

Gene amplification Gene mutation

Normal gene

Chromosome rearrangements

Novel regulatory sequences Fusion transcripts

Fig. Schematic representation of the main mechanism of oncogene activation (from proto-oncogene to oncogene). The normal gene(proto-oncogene) is depicted with its transcribed portion (rectangle). In the case of gene amplification, the latter can be duplicated 100-fold, resulting in an excess of normal protein. A similar situation can occur when following chromosome rearrangement such as translocation, the transcription of the gene is now regulated by novel regulatory sequences belonging to another gene. In the case of point mutation, single amino acid substitutions can alter the biochemical properties of the product, causing, in the example, its constitutive enzymatic activation. Chromosome rearrangement, such as translocation and inversion, can then generate fusion transcripts resulting in chimeric oncogenic proteins.

Tumor Suppressor Gene -

A tumor suppressor gene, or antioncogene, is a gene that protects a cell from one step on the path to cancer. When this gene mutates to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes. The loss of these genes may be even more important than proto-oncogene/ oncogene activation for the formation of many kinds of human cancer cells.

Tumor suppressor genes can be grouped into categories including :- (1) Caretaker genes. (2) Gatekeeper genes. (3) Landscaper 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.

Another important tumor suppressor is the p53 tumor-suppressor protein encoded by the TP53 gene. Abnormalities of the p53 gene can be inherited in Li-Fraumeni syndrome(LFS), which increases the risk of developing various type of cancers.

Tumor suppressor genes play a critical role in regulating when cells are allowed to divided and increase in number. When DNA damage is detected in a cell, some tumor suppressor genes can stop the cell from multiplying until the damage is repaired. Also, specific tumor suppressor genes can stimulate cell with damaged DNA to commit "cell suicide". When tumor suppressor genes don't function correctly, the cells with DNA damage continue to divide and can accumulate. further DNA damage that can eventually lead to the formation of a cancer cell.

Two-hit hypothesis -

Unlike oncogene, 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 damage, 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. 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 single gene, but requiring biallelic mutation. Oncogene mutations, in contrast, generally involve a single allele because they are gain of function mutation. There are notable exceptions to the 'two-hit' rule for tumor suppressor, 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. other tumor-suppressor genes that are exceptions to the 'two-hit' rule are those that exhibit haplo insufficiency for example PTCH in medulloblastoma.

Polycomb group proteins

Oncogenichits

Apoptosis TSGs

Senescence

Oncogenichits Differentiation Benign cancer cells with restricted growth limited proliferative potential

Differentiation acquisition of self- renewal potential Malignant cancer Heterogeneous Polycomb group proteins stem cell malignant stem cell ppproteinprotein tumor