Oncogenes and tumor suppressor genes

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Oncogenes and tumor suppressor genes

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Oncogenes and tumor suppressor genes

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Oncogenes and tumor suppressor genes are classes of genes commonly implicated in the induction of

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A 6-month-old infant boy is brought to the clinic for a well-child visit. His mother expresses concern that  there is inward deviation of his left eye. His older sibling was recently diagnosed with osteosarcoma. Examination looking for the red reflex is shown in the image below:

                   
                                                                                                 Credit: Wikimedia Commons
Which of the following functions is normally performed by the gene product associated with this patient’s condition?

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Content Reviewers:

Rishi Desai, MD, MPH

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.