Studies of tumor viruses capable of infecting normal cells and transforming them into tumor cells led to the initial discovery of oncogenes. The discovery that the Rous sarcoma virus-associated oncogene, Src, originated from the genome of normal chicken cells sug-

From: Endocrinology: Basic and Clinical Principles, Second Edition (S. Melmed and P. M. Conn, eds.) © Humana Press Inc., Totowa, NJ gested the existence of a cellular gene (protooncogene) with oncogenic potential that could be activated by a virus. The compelling evidence that genetic alterations of cellular protooncogenes are involved in human tumor formation came from DNA transfection experiments. DNA from tumor cells was extracted and introduced into normal fibroblast cells. Some transfected cells grew in culture with similar characteristics to transformed cells and when injected into nude mice formed rapidly growing tumor masses. Subsequent isolation and molecular cloning of several oncogenes from transfected cells showed that they are structurally very similar to genes present in DNA of normal cells but contain one or more somatic mutations that occurred during tumor pathogenesis. A subtle change in gene structure even at the single base pair level appeared sufficient to convert a normal cellular protooncogene into a transforming oncogene.

Protooncogenes play important roles in regulating normal cell growth and differentiation, and, to date, more than 200 have been identified. The cellular functions of protooncogenes fall into several groups, includ-

Table 1

Representative Oncogenes in Human Tumors




Mechanism of activation

Properties of gene product


Mammary cacinoma glioblastoma


Growth factor receptor


Papillary thyroid carcinoma


Cell-surface receptor


Stomach carcinoma


Cytoplasmic serine/threonine kinase


Stomach carcinoma

Point mutation

GDP/GTP binding


Bladder carcinoma

Point mutation

Signal transducer



Point mutation

Signal transducer


Lymphomas, carcinomas

Amplification, chromosome translocation

Nuclear transcription factor


Follicular and undifferentiated lymphomas

Chromosome translocation

Cytoplasmic membrane protein


Pituitary tumors

Point mutation

GDP/GTP signal transducer


Pituitary tumors


Securin protein, regulates bFGF

“Adapted from Weinberg (1994).

Ing membrane-associated receptors (e. g., Erb2 and epidermal growth factor receptor), their extracellular ligands (e. g., v-sis and platelet-derived growth factor), cytoplasmic signal transduction molecules (e. g., Src, ras, and raf) or nuclear mitogen-inducible transcription factors (e. g., Jun, fos, myc), and nuclear transcription factors (e. g., estrogen receptor-a, peroxisome pro-liferators-activated receptor-y [PFAR-y]). Table 1 provides representative protooncogenes of these different groups associated with human tumors.

Activation of protooncogenes can result from either a point mutation in the structural region, which encodes for amino acids of a protein, or changes in the regulatory region, which modulates gene expression in response to developmental or physiologic stimuli. Point mutations that activate the ras oncogene are the best characterized mutations found in the former category. These mutations occur most frequently at codons 12, 13, and 61. The ras protein is a guanine nucleotide-binding protein, which acts as a proximal membrane-associated signal transducer resulting in a complex cascade transmitting growth stimulatory signals. Binding to guanosine 5"-triphosphate (GTP) results in ras activation and signal transduction, whereas hydrolysis of bound GTP to guanosine 5"-diphosphate (GDP) by guanosine 5"-triphos-phatase (GTPase) leads to inactivation of ras and termination of signal transduction. The three-dimensional structure of ras has revealed that the amino acid residues most commonly mutated in the ras protein are directly involved in GTP binding and hydrolysis. Thus, mutations in these residues abolished the ability of the ras protein to hydrolyze GTP to GDP, resulting in constitutively activated ras protein, which leads to overexpression of growth stimulatory signals.

Oncogenic conversion of the nuclear protein, myc, results from aberrant expression of the protein rather than a point mutation. A variety of genetic changes can increase the level of myc expression. In Burkitt lymphoma, e. g., a chromosome translocation occurs whereby the myc protooncogene is placed under the control of a regulatory sequence derived from an immunoglobulin gene, uncoupling myc from its normal physiologic modulator and leading to continuous myc expression. In other types of tumor cells, the myc gene is amplified to multiple copies, resulting in a proportional increase in the level of myc protein. In both of these cases, deregulation of myc gene expression results in uncontrolled cell proliferation.

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