Hypoxia Essay

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There are different facets to hypoxia in the human body. A hypoxic situation can be localized to one region one region or generalized to affect the entire body. Additionally, it can be pathological or just an adaptive mechanism that the body uses to regain homeostasis. Traveling to higher altitudes, strenuous exercise, deep sea diving are all examples of normal, non-pathological, generalized hypoxic conditions. A very well known pathological and deleterious example of localized hypoxia is in cancerous tumor growth.

Tumor hypoxia occurs because of the rapid growth and proliferation of cancer cells; the blood supply and thus the oxygen levels cannot keep up with the growth. Which seems as though this would confer a beneficial protective mechanism for the infected individual; if the cancer were starved of oxygen than it should stop proliferating right? Wrong. As amazing as the human body is at maintaining homeostasis without any input or effort to the human on the conscious level, this feature does not just keep humans alive, but allows for damaging processes to occur silently in the body as well. Cancer cells have the ability to alter their metabolism in these hypoxic situations that allows the other wise vulnerable cells to now stay viable. One of the ways tumor cells adapt is through the up regulation of transcription factors such as Hypoxia-Inducible Factors (HIF’s), for example.

HIF-2α is a heterodimeric transcription factor with a beta subunit identified as an Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT). Under normal conditions the HIF-2α subunits are hydroxylated in an iron dependent manner, on two key prolyl-residues by specific prolyl-hydroxylazes. HIF-2α’s are then recognized by the Hippel-Linadau protein (VH...

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...it the tumorgenicity high in the cascade. Although in theory this seemed to be a good idea, in research, this proved to lack specificity and decreased expression of both HIF-1α and HIF-2α, even though HIF-1α does not have an IRE-binding domain. Thus, drawing back on the findings of John McMillian from the seminar series, the discovery of the hydrophobic hole in the core of the HIF-2α protein, can promote further efforts to target and block HIF-2α through binding this core, which would be more specific to HIF-2α vs HIF-1α. Additionally, agents can be designed to not only bind and inhibit conformational changes of this protein but also play a role in down regulating the VHL pathway due to the high prevalence of mutations in this pathway. This would confer both efficacy and specificity in targeting HIF-2α and giving a better prognosis clinically for patients with RCC.

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