HRAS
Protein-coding gene in humans
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Through Enzyme, Gene and Cell membrane
The gene was initially discovered in the Harvey rat sarcoma virus as a viral oncogene (Harvey murine sarcoma virus, Gammaretrovirus Hamursar), hence its name. The gene carried by this virus was later discovered to closely resemble a normal cellular gene found in many animals. From this, it was deduced that the virus had captured this cellular gene at some point in its evolutionary history. Once incorporated, the gene gave the virus the capability to disrupt normal cell growth, turning it into an oncovirus. Incorporation of cellular genes happens regularly in retroviruses; when a key regulatory gene such as HRAS is incorporated, it may become oncogenic as the virus continues to evolve. The benign version in the cellular genome is not directly cancerous, but further mutations can turn it cancerous. As a result, the cellular version is called a proto-oncogene.
Function
GTPase HRas is involved in regulating cell division in response to growth factor stimulation. Growth factors act by binding cell surface receptors that span the cell's plasma membrane. Once activated, receptors stimulate signal transduction events in the cytoplasm, a process in which proteins and second messengers relay signals from outside the cell to the cell nucleus and instruct the cell to grow or divide. The HRAS protein is a GTPase that acts early in many signal transduction pathways and is usually associated with cell membranes due to the presence of an isoprenyl group on its C-terminus. HRAS acts as a molecular on/off switch. Once it is turned on, it recruits and activates proteins necessary for the propagation of the receptor's signal, such as c-Raf and PI 3-kinase. HRAS binds to GTP in the active state and possesses an intrinsic enzymatic activity that cleaves the terminal phosphate of this nucleotide converting it to GDP. Upon conversion of GTP to GDP, HRAS is turned off. The rate of conversion is usually slow but can be sped up dramatically by a GTPase-activating protein (GAP) class (for example, RasGAP). HRAS can in turn bind to proteins of the guanine nucleotide exchange factor (GEF) class (for example SOS1), which forces the release of bound nucleotide. Subsequently, GTP present in the cytosol binds and HRAS-GTP dissociates from the GEF, resulting in HRAS activation.
HRAS is in the Ras family, which also includes two other proto-oncogenes: KRAS and NRAS. These proteins all are regulated in the same manner and appear to differ largely in their sites of action within the cell.
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Clinical significance
Costello syndrome
At least five inherited mutations in the HRAS gene have been identified in people with Costello syndrome. Each of these mutations changes an amino acid in a critical region of the HRAS protein. The most common mutation replaces the amino acid glycine with serine at position 12 (written as Gly12Ser or G12S). The mutations responsible for Costello syndrome lead to the production of an HRAS protein that is permanently active. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This uncontrolled cell division can result in the formation of noncancerous and cancerous tumors. Researchers are uncertain about how mutations in the HRAS gene cause the other features of Costello syndrome (such as intellectual disability, distinctive facial features, and heart problems), but many of the signs and symptoms probably result from cell overgrowth and abnormal cell development during critical periods of growth.
Bladder cancer
HRAS has been shown to be a proto-oncogene. When mutated, proto-oncogenes have the potential to cause normal cells to become cancerous. Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the HRAS gene in bladder cells have been associated with bladder cancer. One specific mutation has been identified in a significant percentage of bladder tumors; this mutation substitutes one amino acid for another in the HRAS protein. Specifically, the mutation replaces the amino acid glycine with the amino acid valine at position 12 (written as Gly12Val, G12V, or H-RasV12). The altered HRAS protein is permanently activated within the cell. This overactive protein directs the cell to grow and divide in the absence of outside signals, leading to uncontrolled cell division and the formation of a tumor. Mutations in the HRAS gene also have been associated with the progression of bladder cancer and an increased risk of tumor recurrence after treatment.
Other cancers
Somatic mutations in the HRAS gene are probably involved in the development of several other types of cancer. These mutations lead to an HRAS protein that is always active and can direct cells to grow and divide without control. Recent studies suggest that HRAS mutations are common in thyroid, salivary duct carcinoma, epithelial-myoepithelial carcinoma, and kidney cancers. A DNA copy-number gain in a segment containing HRAS has been identified as part of a genome-wide pattern, which was found to be correlated with an astrocytoma patient's outcome. The HRAS protein may also be produced at higher levels (overexpressed) in other types of cancer cells.