Oncogenes and tumor suppressor genes

Definitions & Key takeaways

Oncogenes and tumor suppressor genes are types of genes that play a role in the development of cancer. Oncogenes are mutated versions of proto-oncogenes, which normally regulate and promote the cell cycle to progress. Oncogenes end up promoting uncontrolled cell growth and division, causing normal cells to become cancerous. On the other hand, tumor suppressor genes are genes that code for protein products that regulate and slow down the cell cycle, and also promote apoptosis, which is programmed cell death.

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Oncogenes and tumor suppressor genes are classes of genes that code for various proteins that are involved in the progression of the cell cycle.
Oncogenes are actually mutated versions of proto-oncogenes, which are normal genes in charge of positive regulation of the cell-cycle.
So the protein products of proto-oncogenes stimulate cell growth and division - they’re like a gas pedal in a car. Tumor suppressor genes, on the other hand, are in charge of negative regulation of the cell cycle, so their protein products stop its progression and promote apoptosis or cell death.
Tumor suppressor genes are involved in DNA repair mechanisms and inhibiting transcription factors that try to push the cell along in the cell cycle - so they’re like the brake pedal in a car.
Now, the cell cycle is the series of events that a cell goes through as it changes from being one cell into two daughter cells.
The cell cycle has two phases: interphase and mitosis. Interphase is comprised of the G1 phase, during which the cell grows and performs its cell functions, the S phase, during which DNA is replicated, and the G2 phase, during which the cell grows again before entering mitosis.
At the end of G1 and G2, there are cell cycle control points called the G1 and G2 checkpoints, where the cell checks to see if there’s any DNA damage.
The main control point is the G1 checkpoint. If it turns out that there is DNA damage, then the cell can either enter a non-dividing state called the G0 phase, where the DNA repair mechanisms try to fix the problem, or the cell can self-destruct in a process called apoptosis.
Now, if the cell does get the go-ahead at the G1 checkpoint, it enters the S phase. And then if the cell gets past the G2 checkpoint, it enters mitosis, and it divides in two identical daughter cells.
However, once cells differentiate and become mature cells - like liver cells for example - they don’t necessarily go through the cell cycle over and over again.
Actually, cells tend to stay in that G0 phase, and some cells, like neurons, stay in G0 their entire life. Most other cells, however, stay in G0 until they get an external signal like a growth factor.
These growth factors can be secreted by other cells, or by the cell itself, like when there’s a tissue injury, and the remaining cells need to divide to replace the lost cells.
Growth factors bind to growth factor receptors in the cell’s membrane, which activates signal transduction proteins. Ultimately that leads to increased transcription of genes that code for special proteins - like cyclins and cyclin dependent kinases - so more of these proteins are being made.
This is important because whether or not a cell gets cleared at G1 and G2, depends largely on the activity of cyclin dependent kinases, which add phosphate groups to various proteins within the cell.
And these cyclin dependent kinases are, as you might guess, dependent on cyclin proteins. So what happens is that when there’s DNA damage, the cell doesn’t produce cyclins, the cyclin dependent kinases can’t phosphorylate proteins within the cell, and that’s the signal for the cell to halt the cell cycle.
Okay, so proto-oncogenes code for proteins involved in promoting the progression of the cell-cycle. Examples of proto-oncogenes include genes that code for growth factors or growth factor receptors - like the receptor tyrosine kinase or RTK which adds phosphate groups to other proteins.
Another example are genes that code for signal transduction proteins - like Ras genes, that code for Ras proteins. Ras proteins are GTP-ases, meaning that they bind an intracellular GTP molecule, and break it down into GDP and a free phosphate group.
This further activates various cellular pathways, which ultimately result in cell growth, differentiation, and survival.
Another example is the MYC proto-oncogene which codes for a transcription factor that increases expression of cyclins and cyclin dependent kinases.
On the other hand, there are also proto-oncogenes that code for proteins that inhibit apoptosis. An example is bcl-2 which prevents the activation of caspases - the enzymes that actually carries out apoptosis.
Now, proto-oncogenes are normally only active when a cell needs to grow and divide - like you only push the accelerator pedal in a car when you want to speed up.
However, some genetic mutations like translocations, amplifications, or point mutations turn proto-oncogenes into oncogenes.
When a gene is an oncogene it gets overexpressed - meaning, it results in too many proteins, or it means that it codes for hyperactive proteins - which would be kinda like leaving a brick on the gas pedal and going to take a nap in the backseat as the car speeds down the highway.
Cells have two copies of proto-oncogenes; however, if there’s a dominant mutation, that means that just one mutant oncogene copy is enough for the cell to avoid apoptosis and keep growing and dividing uncontrollably.
One example is a type of B cell lymphoma called Burkitt lymphoma, which can result from a chromosomal translocation. When that happens the Myc gene is translocated from chromosome 8 to a spot where it’s right next to the IgH promoter on chromosome 14 which upregulates - or stimulates - its expression.
The Myc protein then induces overexpression of cyclins and cyclin dependent kinases - which leads to uncontrolled cell growth - a lymphoma.
Other oncogenes can result from a fusion gene. For example, the most common cause of chronic myeloid leukemia is a chromosome translocation which results in a Philadelphia chromosome.
A Philadelphia chromosome is one where a portion of chromosome 9’s long arm switches with a portion of chromosome 22’s long arm.
The result is two chromosomes - 9 and 22 - each of which have a bit of one another, and it’s chromosome 22 with a bit of chromosome 9, that’s called the Philadelphia chromosome.
So, in the Philadelphia chromosome, a chromosome 22 gene, called BCR, ends up sitting right next to a chromosome 9 gene, called ABL.
When they’re combined it forms a fusion gene called the BCR-ABL gene, which codes for a protein also called BCR ABL which is always getting expressed.
Now it turns out that BCR ABL has tyrosine kinase activity, meaning that it works as an on-off switch for various cellular functions, including cell division.
Now because the BCR ABL gene is always getting expressed, the result is that myeloid cells keep dividing. This causes a buildup of premature leukocytes in the bone marrow, which eventually spill into the blood - ultimately leading to leukemia!
Now, let’s switch gears to see how tumor suppressor genes work. Tumor suppressor genes code for proteins that stop the cell cycle or promote apoptosis - so they’re the cell cycle’s very own brake pedal.
Like proto-oncogenes, tumor suppressor genes are also normally active throughout the cell cycle, and they code for proteins that halt its progression if there’s any sort of DNA damage.
Some genetic mutations - mainly deletions - turn off the expression of tumor suppressor genes - which leads to a reduction in the number or function of the protein that they encode.
This is a recessive kind of mutation, because it takes two damaged copies for tumor suppressor genes to have no functioning proteins.
When that happens, it’s relatively easy for genetic mutations to accumulate, ultimately allowing the cell to keep growing and dividing uncontrollably.
That’s why a wide variety of cancers feature mutated tumor suppressor genes. For example, the Rb protein is considered a “governor” protein, because it normally inhibits cell proliferation by binding and inactivating a transcription factor called E2F.
Normally, E2F promotes transcription of cyclin E, and cyclin dependent kinase-2, but it can’t do that with Rb holding on to it for dear life.
But, here’s the catch - the Rb protein is only active and clinging to E2F when it isn’t bound to a phosphate. So when a growth factor stimulates a growth signaling pathway, that activates the cyclin dependent kinases which add a phosphate group to Rb, inhibiting it.
Phosphorylated Rb releases E2F, allowing the cell cycle to progress. It’s like bribing the inspector with a phosphate to let the cell keep moving ahead with it’s plans.
In many types of cancer, including retinoblastoma - which gives Rb its name, Rb is inactivated and the loss of the brakes increases the rate of cell division.
Typically, Rb is inactivated by a gene mutation, or by other proteins that specifically inactivate the Rb protein - like protein E7 made by human papillomavirus.
Another example, is the p53 “guardian” protein. P53 is a transcription factor that checks for DNA damage before a cell enters the S phase.
And if there is DNA damage, then specific protein kinases add phosphate groups to p53 - prolonging its life. P53 binds to DNA and promotes transcription of a gene encoding protein called p21.
p21 binds and inhibits the cyclin E-cyclin dependent kinase-2 protein complex, thus preventing passage from the G1 phase to S phase.
This buys a bit of time for DNA repair proteins, which are also expressed thanks to p53 - to get to work. It turns out that P53 is a big deal in the molecular world, and was actually crowned “molecule of the year”, back in 1993!
In fact, studies have found that more than 70% of human cancers are associated with mutations in the p53 gene. When mutations inactivate p53, the cell can no longer repair DNA before it enters the S phase, which means mutations build up, and this can lead to uncontrolled cell division.
Alright, as a quick recap, oncogenes are actually mutated versions of proto-oncogenes, which are normal genes that act like the accelerator pedal on the cell cycle - so they stimulate cell growth and division.
Their protein products are growth factors, growth factor receptors, signal transduction proteins, transcription factors, and apoptosis regulators.
Tumor suppressor genes are like the brake pedals on the cell cycle - they inhibit progression to mitosis and/or promote apoptosis.
They include governor and guardian proteins like Rb and p53.