KRAS is a protein responsible for regulating cell division in the human body. It is encoded by v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog or more often known as the KRAS oncogene. It is a GTPase signal transducer, capable of activating itself on and off (KRAS 2011). When GTP is bound to KRAS, KRAS protein is activated by signals from its own cell surface receptors. When KRAS hydrolyzes GTP back to GDP, it causes itself to become inactivated (Kranenburg 2005). Recently, KRAS protein has become a major topic of interest. Research has shown that there is a link between the presence of mutated KRAS proteins and cancers such as pancreatic, thyroid, colorectal, and lung (Kranenburg 2005) and diseases such as Noonan syndrome, CFC syndrome (Zenker 2007), and Adult Acute Myeloid Leukemia (Ebtesam 2009).
Mutated KRAS proteins are often caused by single point mutations in the highly activated KRAS oncogenes. These result in amino acid substitutions that lead to proteins fixed in an activated GTP state, incapable of hydrolyzing GTP back to GDP. Due to their association, mutated KRAS proteins are useful in early detection and screening for its related cancers and diseases. Aptamers (nucleic acid oligomers such as RNA or ssDNA) can be selected to distinguish KRAS proteins from mutated KRAS proteins and aid with screening and diagnostic purposes.
In conclusion, anti-KRAS aptamers can bind to KRAS proteins with great sensitivity and selectivity. This ability of aptamers to bind specifically to its protein will allow for the distinction between mutated and non mutated KRAS proteins. If mutated KRAS proteins are identified in a patient's tissue sample, then further testing should be conducted.
Specific Aim 1: Selection of RNA aptamers against KRAS for Detection of Mutated KRAS Proteins
Because of a correlation between the presence of mutated KRAS proteins and its related diseases and cancers, anti-KRAS aptamers can be selected to screen for these cancers and diseases in humans. Human tissue samples containing KRAS proteins can be exposed to anti-KRAS aptamers to determine whether or not the KRAS proteins can bind to its aptamers. If a majority of the proteins are found not to have bound to its aptamers, then there are possibilities for mutated KRAS proteins in the tissue samples and thus signaling for further testing in patients for KRAS proteins’ related cancers and diseases.
Figure 1: Mutated KRAS proteins are often found near certain cancers and diseases. Screening for these mutated proteins by using anti-KRAS aptamers can result in earlier detection of cancer or disease.
KRAS protein can be bought at Abcam at 100 ug for $260. Its catalog number is ab96817.
Ebtesam I., Ahmad, M.D. (2009). “The Prognostic Impact of K-RAS Mutations in Adult Acute Myeloid Leukemia Patients Treated with High Dose Cytarabine” Journal of the Egyptian Nat. Cancer Inst. 21(4):343-350.
Kranenburg, O. (2005) “The KRAS oncogene: Past, present, and future.” Biochimica et Biophysica Acta 1756: 81–82.
"KRAS." Genetics Home Reference. U.S. National Library of Medicine, Mar 2011.
Zenker, M., Lehmann, K., Schulz, A.L., Barth, H. (2007). “Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.” J Med Genet 44: 131–135
Melissa Tung
3 comments:
Sounds like a cool target!
-Zoe White
This sounds really neat. Good luck!
this is a great idea!! another thing to consider would be inhibition of the function of this protein... not only could you detect the mutated form, but you may also be able to inhibit it!
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