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When cells are undergoing hypoxia usually occurred in the core of a solid tumor significant changes including suppression of ATP consumption stalled protein translation decrease in RNA synthesis and significant changes in genes transcription were observed Hochachka et al 1996 Hypoxia also induces alteration in energy metabolism and other systemic changes which are involved in glucose transport glycolysis erythropoiesis angiogenesis and vasodilation to reduce the impact of O2 deprivation and allowing adaptation to low energy consumption at low O2 levels Wenger 2002 Alteration of hypoxia-responsive genes is initially mediated by the hypoxia-inducible factor HIF complex consisting of HIF-1 and HIF-1 ARNT heterodimers Wang and Semenza 1993 HIF-1 is a basic helix-loop-helix transcription factor that is encoded by the HIF1A gene During normoxia 21 O2 the HIF-1 is hydroxylated at the proline residues 402 and 577 by the prolyl hydroxylase domain-containing PHD proteins Jaakkola et al 2001 Hydroxylated HIF-1 is then ubiquitinated by the Von Hippel-Lindau pVHL a tumor suppressor protein and subjected to degradation by the 26S proteosome Cockman et al 2000 The HIF-1 is stabilized under hypoxia when proline hydroxylation of the HIF-1 is suppressed thereby preventing the degradative association with the pVHL When the stabilized HIF-1 translocates to the nucleus the HIF-1 and ARNT dimerize results in transactivation of hypoxia-responsive genes through binding at the hypoxia response elements HREs Jiang et al 1996 Overexpression of the HIF-1 protein has shown to be a marker of poor prognosis in primary breast cancer patients Schindl et al 2002 This has been attributed to a number of adaptive responses such as the switching of metabolism to less oxygen-dependent glycolytic pathways induction of cancer stem cell characteristics loss of reactive oxygen species and shutting down of mitochondrial apoptotic signaling centres all of which promote cancer progression in low oxygen conditions Besides the HIF-1 the HIF-2 another basic helix-loop-helix transcription factor induced by hypoxia mediates chronic phase hypoxic gene activation which is different from the HIF-1 that
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