Sandbox Reserved 598: Difference between revisions
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Mutations in Jak2 can result in the erythropoietin receptor being activated all the time. Due to lack of auto-inhibition of the JAK2 enzyme because of this activating mutation the receptor is effectively switched to the ‘on’ position indefinitely, constantly over-produce cells. This type of mutation has been found to occur in a nucleotide substitution of valine to phenylalanine and is therefore termed, V617F. The active conformation of Jak2 is likely to be mimicked by the Jak2-V617F mutant and this thereby results in either oncogenesis, polycythemia or other hematopoietic disorders. <ref>Gnanasambandan, K., & Sayeski, P. (2011). A structure-function perspective of jak2 mutations and implications for alternate drug design strategies: the road not taken. Department of Physiology and Functional Genomics, University of Florida College of Medicine, 18(30), 59-73. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21864276 http://www.ncbi.nlm.nih.gov/pubmed/21864276 </ref> Other mutant conformations, such as the Y613E mutant, failed to undergo complete conformational changes leading to its activation. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/ | Mutations in Jak2 can result in the erythropoietin receptor being activated all the time. Due to lack of auto-inhibition of the JAK2 enzyme because of this activating mutation the receptor is effectively switched to the ‘on’ position indefinitely, constantly over-produce cells. This type of mutation has been found to occur in a nucleotide substitution of valine to phenylalanine and is therefore termed, V617F. The active conformation of Jak2 is likely to be mimicked by the Jak2-V617F mutant and this thereby results in either oncogenesis, polycythemia or other hematopoietic disorders. <ref>Gnanasambandan, K., & Sayeski, P. (2011). A structure-function perspective of jak2 mutations and implications for alternate drug design strategies: the road not taken. Department of Physiology and Functional Genomics, University of Florida College of Medicine, 18(30), 59-73. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21864276 http://www.ncbi.nlm.nih.gov/pubmed/21864276 </ref> Other mutant conformations, such as the Y613E mutant, failed to undergo complete conformational changes leading to its activation. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/ | ||
(7) Kirwan, J. (02, 2011 03). Janus incarnate. Retrieved from http://rense.com/general92/janus.htm </ref> A diagramed example of how normal Jak2 receptors work, as well as how this mutation works mechanically can be seen on figure 4. | (7) Kirwan, J. (02, 2011 03). Janus incarnate. Retrieved from http://rense.com/general92/janus.htm </ref> A diagramed example of how normal Jak2 receptors work, as well as how this mutation works mechanically can be seen on figure 4. | ||
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'''Conditions associated with Jak2 mutations:''' As Janus Kinase 2 has a significant role in hematopoiesis, the formation and development of blood cells, mutations in the protein most commonly result in constitutive kinase activation which lead to oncogenesis. Some of the cancers associated with such mutations have been found to be myeloid leukemia, lymphoid leukemia, polycythemia vera, along with other myeloproliferative neoplasms. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/ </ref> While there are many different genetic mutations which are resultant of leukemias, 85% of patients diagnosed with polycythemia vera are found to have the mutation in their Jak2 protein. <ref> http://www.mayoclinic.com/health/polycythemia-vera/DS00919 </ref> There are currently many therapies for differing forms of leukemia, some of which include cytoreductive medications such as hydroxyurea or agrylin, to suppress the bone marrow’s ability to make blood cells, cell destructive medications like cytoxin which act as oral chemotheraputic agents, interferon treatments to stimulate the patient's immune response to fight and kill overproduction or white and red blood cells. Finally traditional chemotherapy is commonly used, as well, for both leukemias as well as progressive polycythemia vera. <ref> http://m.cancer.gov/topics/treatment/bycancer/adultAML/Patient </ref> <ref> http://www.mayoclinic.com/health/chronic-lymphocytic-leukemia/DS00565 </ref> <ref> http://www.mayoclinic.com/health/polycythemia-vera/DS00919 </ref> <ref> Medscape Reference (01, 2012, 10) Polycythemia Treatment and Management. Retrieved from: http://emedicine.medscape.com/article/205114-treatment </ref> While there are a few Jak2 inhibitors already in use which use competitive inhibition for ATP binding pockets, they are not extremely effective due to non-specificity. <ref> Gnanasambandan, K., & Sayeski, P. (2011). A structure-function perspective of jak2 mutations and implications for alternate drug design strategies: the road not taken. Department of Physiology and Functional Genomics, University of Florida College of Medicine, 18(30), 59-73. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21864276 http://www.ncbi.nlm.nih.gov/pubmed/21864276 </ref> | |||
