Identoification and Types of Oncogene

An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated or expressed at high levels. Most normal cells will undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered and malfunctioning

1. ONCOGENE

2. Oncogenes are mutated genes that can contribute to the development of  cancer . In their non-mutated state, everyone has genes which are referred to as proto-oncogenes. When proto-oncogenes are mutated or increased in numbers (amplification) due to DNA damage (such as exposure to carcinogens), the proteins produced by these genes can affect the growth, proliferation, and survival of the cell, and potentially result in the formation of a malignant tumor . There are many checks and balances in place, and the development of cancer most often requires mutations or other genetic changes in both oncogenes and tumor suppressor genes (genes that produce proteins that either repair or eliminate damaged cells).

3. HISTORY

4. The concept of oncogenes had been theorized for over a century, but the first oncogene was not isolated until 1970 when an oncogene was discovered in a cancer-causing virus called the rous sarcoma virus (a chicken retrovirus). It was well known that some viruses, and other microorganisms, can cause cancer and in fact, 20% to 25% of cancers worldwide and around 10% in the United States, are caused by these invisible organisms. The majority of cancers, however, do not arise in relation to an infectious organism, and in 1976 many cellular oncogenes were found to be mutated proto-oncogenes; genes normally present in humans. Since that time much has been learned about how these genes (or the proteins they code for) function, with some of the exciting advances in cancer treatment derived from targeting the oncoproteins responsible for cancer growth.

5. DISCOVERY AND IDENTIFICATION

6. The first oncogenes were discovered through the study of retroviruses, RNA tumor viruses whose genomes are reverse-transcribed into DNA in infected animal cells. During the course of infection, retroviral DNA is inserted into the chromosomes of host cells. The integrated retroviral DNA, called the provirus, replicates along with the cellular DNA of the host. Transcription of the DNA provirus leads to the production of viral progeny that bud through the host cell membrane to infect other cells. Two categories of retroviruses are classified by their time course of tumor formation in experimental animals. Acutely transforming retroviruses can rapidly cause tumors within days after injection. These retroviruses can also transform cell cultures to the neoplastic phenotype. Chronic or weakly oncogenic retroviruses can cause tissue-specific tumors in susceptible strains of experimental animals after a latency period of many months. Although weakly oncogenic retroviruses can replicate in vitro, these viruses do not transform cells in culture.

7. Retroviral oncogenes are altered versions of host cellular protooncogenes that have been incorporated into the retroviral genome by recombination with host DNA, a process known as retroviral transduction.  This surprising discovery was made through study of the Rous sarcoma virus (RSV) (Figure)

8. RSV is an acutely transforming retrovirus first isolated from a chicken sarcoma over 80 years ago by Peyton Rous. Studies of RSV mutants in the early 1970s revealed that the transforming gene of RSV was not required for viral replication. Molecular hybridization studies then showed that the RSV transforming gene (designated v- src ) was homologous to a host cellular gene (c- src ) that was widely conserved in eukaryotic species. Studies of many other acutely transforming retroviruses from fowl, rodent, feline, and nonhuman primate species have led to the discovery of dozens of different retroviral oncogenes. In every case, these retroviral oncogenes are derived from normal cellular genes captured from the genome of the host. Viral oncogenes are responsible for the rapid tumor formation and efficient in vitro transformation activity characteristic of acutely transforming retroviruses.

9. In contrast to acutely transforming retroviruses, weakly oncogenic retroviruses do not carry viral oncogenes. These retroviruses, which include mouse mammary tumor virus (MMTV) and various animal leukemia viruses, induce tumors by a process called insertional mutagenesis (Figure)

10. This process results from integration of the DNA provirus into the host genome in infected cells. In rare cells, the provirus inserts near a protooncogene. Expression of the protooncogene is then abnormally driven by the transcriptional regulatory elements contained within the long terminal repeats of the provirus. In these cases, proviral integration represents a mutagenic event that activates a protooncogene. Activation of the protooncogene then results in transformation of the cell, which can grow clonally into a tumor .

11. The long latent period of tumor formation of weakly oncogenic retroviruses is therefore due to the rarity of the provirus insertional event that leads to tumor development from a single transformed cell. Insertional mutagenesis by weakly oncogenic retroviruses, first demonstrated in bursal lymphomas of chickens, frequently involves the same oncogenes (such as myc , myb , and erb B) that are carried by acutely transforming retroviruses. In many cases, however, insertional mutagenesis has been used as a tool to identify new oncogenes, including int-1, int-2, pim-1, and lck.22

12. The demonstration of activated protooncogenes in human tumors was first shown by the DNA-mediated transformation technique. This technique, also called gene transfer or transfection assay, verifies the ability of donor DNA from a tumor to transform a recipient strain of rodent cells called NIH 3T3, an immortalized mouse cell line (Figure)

13. This sensitive assay, which can detect the presence of single-copy oncogenes in a tumor sample, also enables the isolation of the transforming oncogene by molecular cloning techniques. After serial growth of the transformed NIH 3T3 cells, the human tumor oncogene can be cloned by its association with human repetitive DNA sequences. The first human oncogene isolated by the gene transfer technique was derived from a bladder carcinoma. Overall, approximately 20% of individual human tumors have been shown to induce transformation of NIH 3T3 cells in gene-transfer assays. The value of transfection assay was recently reinforced by the laboratory of Robert Weinberg, which showed that the ectopic expression of the telomerase catalytic subunit (hTERT), in combination with the simian virus 40 large T product and a mutated oncogenic H- ras  protein, resulted in the direct tumorigenic conversion of normal human epithelial and fibroblast cells.

14. Many of the oncogenes identified by gene-transfer studies are identical or closely related to those oncogenes transduced by retroviruses. Most prominent among these are members of the  ras  family that have been repeatedly isolated from various human tumors by gene transfer. A number of new oncogenes (such as  neu ,  met , and  trk ) have also been identified by the gene-transfer technique. In many cases, however, oncogenes identified by gene transfer were shown to be activated by rearrangement during the experimental procedure and are not activated in the human tumors that served as the source of the donor DNA, as in the case of  ret  that was subsequently found genuinely rearranged and activated in papillary thyroid carcinomas.

15. Chromosomal translocations have served as guideposts for the discovery of many new oncogenes. Consistently recurring karyotypic abnormalities are found in many hematologic and solid tumors . These abnormalities include chromosomal rearrangements as well as the gain or loss of whole chromosomes or chromosome segments. The first consistent karyotypic abnormality identified in a human neoplasm was a characteristic small chromosome in the cells of patients with chronic myelogenous leukemia . Later identified as a derivative of chromosome 22, this abnormality was designated the Philadelphia chromosome, after its city of discovery. The application of chromosome banding techniques in the early 1970s enabled the precise cytogenetic characterization of many chromosomal translocations in human leukemia , lymphoma, and solid tumors .

16. The subsequent development of molecular cloning techniques then enabled the identification of protooncogenes at or near chromosomal breakpoints in various neoplasms. Some of these protooncogenes, such as  myc  and  abl , had been previously identified as retroviral oncogenes. In general, however, the cloning of chromosomal breakpoints has served as a rich source of discovery of new oncogenes involved in human cancer.

17. TYPES AND EXAMPLES

18. Different types of oncogenes have different effects on growth (mechanisms of action), and to understand these it's helpful to look at what is involved in normal cell proliferation (the normal growth and division of cells). Most oncogenes regulate the proliferation of cells, but some inhibit differentiation (the process of cells becoming unique types of cells) or promote survival of cells (inhibit programmed death or apoptosis). Recent research also suggests that proteins produced by some oncogenes work to suppress the immune system, reducing the chance that abnormal cells will be recognized and eliminated by immune cells such as T-cells. While there are more than 100 different functions of oncogenes, they can be broken down into several major types that transform a normal cell to a self-sufficient cancer cell. It's important to note that several oncogenes produce proteins that function in more than one of these areas.

19. Growth Factors Some cells with oncogenes become self-sufficient by making (synthesizing) the growth factors to which they respond. The increase in growth factors alone doesn't lead to cancer but can cause rapid growth of cells that raises the chance of mutations. An example includes the proto-oncogene SIS, that when mutated results in the overproduction of platelet-derived growth factor (PDGF). Increased PDGF is present in many cancers, particularly bone cancer (osteosarcoma) and one type of brain tumor .

20. Growth Factor Receptors Oncogenes may activate or increase growth factor receptors on the surface of cells (to which growth factors bind). One example includes the HER2 oncogene that results in a significantly increased number of HER2 proteins on the surface of breast cancer cells. In roughly 25% of breast cancers, HER2 receptors are found in numbers 40 times to 100 times higher than in normal breast cells. Another example is the epidermal growth factor receptor (EGFR) found in around 15% of non-small cell lung cancers.

21. Signal Transduction Proteins Other oncogenes affect proteins involved in transmitting signals from the receptor of the cell to the nucleus. Of these oncogenes, the ras family is most common (KRAS, HRAS, and NRAS) found in roughly 20% of cancers overall. BRAF in melanoma is also in this category. Regulators of Apoptosis Oncogenes may also produce oncoproteins that reduce apoptosis (programmed cell death) and lead to prolonged survival of the cells. An example is Bcl-2, an oncogene that produces a protein associated with the cell membrane that prevents cell death (apoptosis).

22. Non-Receptor Protein Kinases Non-receptor protein kinases are also included in the cascade that carries the signal to grow from the receptor to the nucleus. A well-known oncogene involved in chronic myelogenous leukemia is the Bcr-Abl gene (the Philadelphia chromosome ) caused by a translocation of segments of chromosome 9 and chromosome 22. When the protein produced by this gene, a tyrosine kinase, is continually produced it results in a continuous signal for the cell to grow and divide.

23. Transcription Factors Transcription factors are proteins that regulate when cells enter, and how they progress through the cell cycle. An example is the Myc gene that is overly active in cancers such as some leukemias and lymphomas. Cell Cycle Control Proteins Cell cycle control proteins are products of oncogenes that can affect the cell cycle in a number of different ways. Some, such as cyclin D1 and cyclin E1 work to progress through specific stages of the cell cycle, such as the G1/S checkpoint.

24. THA NK YOU