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 undergo a preprogrammed rapid cell death (apoptosis) if critical functions are altered and then malfunction. Activated oncogenes can cause those cells designated for apoptosis to survive and proliferate instead. Most oncogenes began as proto-oncogenes, normal genes involved in cell growth and proliferation or inhibition of apoptosis. If, through mutation, normal genes promoting cellular growth are up-regulated (gain-of-function mutation), they predispose the cell to cancer and are termed oncogenes. Usually, multiple oncogenes, along with mutated apoptotic or tumor suppressor genes, act in concert to cause cancer. Oncogenes are a physically and functionally diverse set of genes, and as a result, their protein products have pleiotropic effects on a variety of intricate regulatory cascades within the cell. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many cancer drugs target the proteins encoded by oncogenes. The resultant protein encoded by an oncogene is termed oncoprotein. Oncogenes play an important role in the regulation or synthesis of proteins linked to tumorigenic cell growth. Some oncoproteins are accepted and used as tumor markers.

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 undergo a preprogrammed rapid cell death (apoptosis) if critical functions are altered and then malfunction. Activated oncogenes can cause those cells designated for apoptosis to survive and proliferate instead. Most oncogenes began as proto-oncogenes, normal genes involved in cell growth and proliferation or inhibition of apoptosis. If, through mutation, normal genes promoting cellular growth are up-regulated (gain-of-function mutation), they predispose the cell to cancer and are termed oncogenes. Usually, multiple oncogenes, along with mutated apoptotic or tumor suppressor genes, act in concert to cause cancer. Oncogenes are a physically and functionally diverse set of genes, and as a result, their protein products have pleiotropic effects on a variety of intricate regulatory cascades within the cell. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many cancer drugs target the proteins encoded by oncogenes. The resultant protein encoded by an oncogene is termed oncoprotein. Oncogenes play an important role in the regulation or synthesis of proteins linked to tumorigenic cell growth. Some oncoproteins are accepted and used as tumor markers.

History

The theory of oncogenes was foreshadowed by the German biologist Theodor Boveri in his 1914 book Zur Frage der Entstehung Maligner Tumoren (Concerning the Origin of Malignant Tumors) in which he predicted the existence of oncogenes (Teilungsfoerdernde Chromosomen) that become amplified (im permanenten Übergewicht) during tumor development. Later on, the term "oncogene" was rediscovered in 1969 by National Cancer Institute scientists George Todaro and Robert Huebner. The first confirmed oncogene was discovered in 1970 and was termed SRC (pronounced "sarc" as it is short for sarcoma). SRC was first discovered as an oncogene in a chicken retrovirus. Experiments performed by Dr. G. Steve Martin of the University of California, Berkeley demonstrated that SRC was indeed the gene of the virus that acted as an oncogene upon infection. The first nucleotide sequence of v-Src was sequenced in 1980 by A.P. Czernilofsky et al. In 1976, Drs. , J. Michael Bishop and Harold E. Varmus of the University of California, San Francisco demonstrated that oncogenes were activated proto-oncogenes as is found in many organisms, including humans. Bishop and Varmus were awarded the Nobel Prize in Physiology or Medicine in 1989 for their discovery of the cellular origin of retroviral oncogenes. Dr. Robert Weinberg is credited with discovering the first identified human oncogene in a human bladder cancer cell line. The molecular nature of the mutation leading to oncogenesis was subsequently isolated and characterized by the Spanish biochemist Mariano Barbacid and published in Nature in 1982¹. Dr. Barbacid spent the following months extending his research, eventually discovering that the oncogene was a mutated allele of HRAS and characterizing its activation mechanism.

Classification

There are several systems for classifying oncogenes, but there is not yet a widely accepted standard. They are sometimes grouped both spatially (moving from outside the cell inwards) and chronologically (parallelling the "normal" process of signal transduction). There are several categories that are commonly used: Additional oncogenetic regulator properties include: Growth factors are usually secreted by either specialized or non-specialized cells to induce cell proliferation in themselves, nearby cells, or distant cells. An oncogene may cause a cell to secrete growth factors even though it does not normally do so. It will thereby induce its own uncontrolled proliferation (autocrine loop), and proliferation of neighboring cells, possibly leading to tumor formation. It may also cause production of growth hormones in other parts of the body. Receptor tyrosine kinases add phosphate groups to other proteins in order to turn them on or off. Receptor kinases add phosphate groups to receptor proteins at the surface of the cell (which receives protein signals from outside the cell and transmits them to the inside of the cell). Tyrosine kinases add phosphate groups to the amino acid tyrosine in the target protein. They can cause cancer by turning the receptor permanently on (constitutively), even without signals from outside the cell. Ras is a small GTPase that hydrolyses GTP into GDP and phosphate. Ras is activated by growth factor signaling (i.e., EGF, TGFbeta) and acting as a binary switch (on/off) in growth signaling pathways. Downstream effectors of Ras include three mitogen-activated protein kinases Raf a MAP Kinase Kinase Kinase (MAPKKK), MEK a MAP Kinase Kinase (MAPKK), and ERK a MAP Kinase(MAPK), which in turn regulate genes that mediate cell proliferation.

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