The HRAS gene was first identified in the early 1960s by J. J. Harvey, who discovered the Harvey strain of murine sarcoma virus (HaMSV) in rats . The viral oncogene, v-Ha-ras, was found to be homologous to the cellular proto-oncogene, c-Ha-ras, which is present in humans. The human homolog of this gene is located on the short arm of chromosome 11 at position 15.5 (11p15.5) .
HRAS encodes a protein known as p21ras, which functions as a molecular switch in various signal transduction pathways. This protein is involved in regulating cell division in response to growth factor stimulation . The HRAS protein binds to guanosine triphosphate (GTP) in its active state and possesses intrinsic GTPase activity, which allows it to hydrolyze GTP to guanosine diphosphate (GDP), thereby turning itself off .
The activation and inactivation of HRAS are tightly regulated by accessory proteins such as GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). GAPs accelerate the hydrolysis of GTP to GDP, while GEFs facilitate the exchange of GDP for GTP, thus reactivating HRAS .
Mutations in the HRAS gene can lead to its constitutive activation, resulting in uncontrolled cell proliferation and tumor formation. Such mutations are implicated in various types of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma . HRAS is one of the three major Ras genes, along with KRAS and NRAS, that are frequently mutated in human cancers .
The HRAS gene is also associated with several genetic disorders. For instance, mutations in HRAS cause Costello syndrome, a condition characterized by distinctive facial features, developmental delays, and an increased risk of tumor formation . Understanding the function and regulation of HRAS is crucial for developing targeted therapies for cancers and other diseases associated with its mutations.
Ongoing research aims to develop inhibitors that specifically target the HRAS protein and its downstream signaling pathways. These therapeutic approaches hold promise for treating cancers driven by HRAS mutations. Additionally, recombinant forms of the HRAS protein are used in various experimental settings to study its function and interactions with other cellular proteins.