Wednesday, June 6, 2012

Proto-Oncogenes

● What are Proto-Oncogenes

Proto-oncogenes are a subgroup of genes that, when mutated, are directly involved in the development of cancer. The mutation of proto-oncogenes causes normal cells to mutate into cancerous cells. A mutation of a proto-oncogene is a dominant type of mutation, and once the proto-oncogene becomes mutated it is classified as an oncogene. Before a proto-oncogene becomes affected it is often responsible for encoding protein function related to cell division as well as inhibition of cell differentiation and cellular apoptosis. These are functions that are pivotal for normal physiologic function and the mutation feeds off of this relationship. When the oncogene takes over, it typically ramps up these functions and thus increases the overall rate of cancer cell development without an inhibitory control present to halt the production of the cancerous cells. Given this fact, oncogenes are the main target in anti-cancer drug design.


● Transformation From Proto-Oncogenes to Oncogenes

As it is known today, there are over 40 different proto-oncogenes within the human genome. The transformation from a proto-oncogene to an oncogene is a very specific mutation. Oncogenes are a byproduct of mutations that increase the expression level of a proto-oncogene because these are the type of mutations that are going to lead to the greatest form of cancer cell proliferation. There are a number of genetic mechanisms that are correlated with proto-oncogene mutations,
such as:

  1. Point mutation, deletion, or insertion resulting in hyperactive gene product.
  2. Point mutation, deletion, or insertion within a promoter region of proto-oncogene that regulates transcription.
  3. Gene amplification leading to extra chromosomal copies of the mutated gene.
  4. Translocation events that move the proto-oncogene to a new locus leading to higher expression.
  5. Chromosomal translocations leading to proto-oncogene fusion and a secondary gene, resulting in a fusion protein with oncogenic activity.


(Image from: Cancer Genetics - Oncogenes)



● Oncogenic Examples

One place where proto-oncogenes have a large role is the coding of cell surface receptors, which act as a communication conduit between the extracellular environment and the intracellular environment. These receptors are composed of three separate parts that function simultaneously in order to provide optimal signaling. The extracellular region is similar to an antenna in that it collects an outside signal from the environment. The transmembrane region spans the length of the plasma membrane. The intracellular region possesses its own enzymatic activity and interacts with other proteins found within the cell.
A cell responds to signals outside from the extracellular environment in order to participate in proper growth and division. This occurs through ligand binding to the extracellular component of the transmembrane receptors. Ligands often take the form of growth factors to stimulate growth or angiogenic factors, which stimulate vascularization. Comformational changes occur with the binding of the ligand, which leads to the activation of intracellular domain resulting in a cascade effect affecting cell growth, proliferation, vascularization, or apoptosis. A specific example of this includes epidermal growth factor and epidermal growth factor receptor, which are responsible for growth factor mediation.

Proto-oncogenes are also responsible for coding proteins that may have a downstream effect resulting in stimulation of cell growth and division. A specific example of this is the RAS gene family, HRAS and KRAS. Along the same lines, there are some proto-oncogenes that are responsible for continuing cells through the cell cycle when specific signals are received by receptors. When these proto-oncogenes are overly expressed or expression is turned on at the wrong time, cancer cells begin to appear.

Oncogenes can also be expressed through translocation events occurring at the chromosome level. The best example of this is the Philadelphia chromosome. In this example, a crossover event occurs between chromosome 9 and chromosome 22. This results in interaction between the BCR gene found on chromosome 22 with the ABL1 gene found on chromosome 9. The fusion of these genes results in the production of the protein with high protein tyrosine kinase activity. If this expression goes about unregulated, there are a number of other proteins involved in cell cycle regulation that are activated to stimulate cell division. This is the gene that is often associated with numerous forms of leukemia.

Proto-oncogenes are important to understand in the development and treatment of cancer and through further research, cancer treatment can continue to progress.


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