9.7
Cancer-Critical Genes I: Proto-oncogenes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern…
Cancer-critical genes are a group of genes that, upon mutation or alteration, contribute to the development of cancer.
These genes can be categorized into two major classes based on how the mutation affects gene activity - proto-oncogenes and tumor-suppressor genes.
Under normal conditions, proto-oncogenes encode for proteins that act as signals for cell division. A gain-of-function mutation in the proto-oncogenes converts them into an overactive form called oncogenes.
The activation of oncogenes leads to overexpression of the cell-growth proteins resulting in uncontrolled cell proliferation and, hence, the formation of a tumor.
Gain-of-function mutations in proto-oncogenes are usually dominant, and even a single mutation can transform them into an oncogene.
For example, the proto-oncogene Ras encodes for an intracellular signal-transduction protein, Ras. Upon activation, Ras switches ON the cell growth signaling cascades. Upon mutation, the Ras gene turns into an oncogene and produces a mutated protein. This mutated Ras switches ON the signaling pathways, even in the absence of any activation signals, leading to the uncontrolled growth of cells and, ultimately, tumor formation.
View the full transcript and gain access to JoVE Core videos
Q1: What are proto-oncogenes and what do they normally do in cells?
Proto-oncogenes are normal genes that encode proteins controlling cell division and growth signaling. Under normal conditions, these genes regulate cellular growth through signal-transduction pathways that respond to activation signals. When functioning properly, proto-oncogenes maintain controlled cell proliferation necessary for healthy tissue development and maintenance.
Q2: How do gain-of-function mutations convert proto-oncogenes into oncogenes?
Gain-of-function mutations alter proto-oncogenes to produce overactive proteins that continuously activate growth signaling pathways without requiring external activation signals. This constant activation leads to uncontrolled cell proliferation. These mutations are typically dominant, meaning even a single mutated copy can transform the proto-oncogene into a cancer-causing oncogene.
Q3: What happens to cells when the Ras proto-oncogene becomes mutated?
When the Ras proto-oncogene mutates, it produces a defective protein that permanently switches on cell growth signaling cascades. Unlike normal Ras, the mutated version remains active even without activation signals, causing cells to divide uncontrollably and eventually form tumors through continuous growth stimulation.
Q4: What is the main difference between proto-oncogenes and tumor suppressor genes?
Proto-oncogenes cause cancer when they become overactive through gain-of-function mutations, while cancer-critical genes ii tumor suppressor genes cause cancer when they lose function or become inactivated. Proto-oncogenes drive excessive cell growth when mutated, whereas tumor suppressors normally restrain cell division and must be disabled for cancer to develop.
Q5: Why are gain-of-function mutations in proto-oncogenes considered dominant?
Gain-of-function mutations in proto-oncogenes are dominant because a single mutated copy produces enough overactive protein to drive uncontrolled cell growth. The mutated allele does not require a normal copy to function, so even heterozygous cells with one mutated proto-oncogene can develop into tumors without needing both copies to be affected.
Q6: What are common examples of proto-oncogenes found in humans?
Common human proto-oncogenes include Ras, HER2, Myc, and Cyclin D. These genes normally regulate essential cellular processes like growth signaling and cell cycle progression. When mutated, any of these proto-oncogenes can contribute to tumor formation by producing proteins that drive excessive cell proliferation.
Q7: How do mutations in proto-oncogenes lead to tumor formation?
Mutations in proto-oncogenes cause overexpression of cell-growth proteins, resulting in uncontrolled cell proliferation. Cells with activated oncogenes continuously receive growth signals regardless of normal regulatory mechanisms. This persistent proliferation allows abnormal cells to accumulate and eventually develop into tumors through continuous, unregulated division.