Oxygen-dependent degradation

HIF-a contains a large, central regulatory region. The oxygen-dependent degradation domain of HIF-a contains two sites of... 

HIF-la and HIF-2a have the same domain architecture and common mechanisms for DNA binding, dimerization, oxygen-dependent degradation (NODD and CODD domains), and transactivation domains. The sequences of these domains are related closely but contain differences that may have functional consequences (e.g., with respect to HIF hydroxylase selectivity). The interdomain sequences are related less closely, and the differences may enable differential binding of regulatory proteins to HIF-la and HIF-2a. HIF-3a is more markedly different from the other two HIF-a isoforms as it apparently has no functional NODD domain, and only the CODD domain within the N-terminal TAD has been identified. Additionally, HIF-3a lacks the C-TAD that exists in both HIF-la and HIF-2a. (28). Relatively little is known about the importance of HIF-3a as compared with the intensively investigated HIF-l/2a isoforms. 

Flashman E, Bagg EAL, Chowdhury R, Mecinovic J, Loenarz C, McDonough MA, Hewitson KS, Schofield CJ. Kinetic rationale for selectivity towards the N- and C-terminal oxygen dependent degradation domain substrates mediated by a loop region of HIF prolyl hydroxylases. J. Biol. Chem. 2008 582 434-438. 

Both NO and CO may affect (and be involved in) oxygen-dependent phenomena. Accordingly, in vitro experiments have demonstrated that elevated levels of NO or CO can diminish effects of hypoxia on gene transcription. These molecules both activated the internal oxygen-dependent degradation domain and repressed the C-terminal transactivation domain of HIF resulting in less HIF-la that can bind to DNA (Huang et al., 1999). On the other hand, in vivo experiments have demonstrated that NO is one of the modulators of the hypoxic ventilatory response mediated by the rostral mediolateral medulla (de Paula and Branco, 2003). It is not clear at present, whether different cell types respond in a different manner. 

Since the proteasome mediates the oxygen-dependent degradation of HIE-lct protein, natural product-based proteasome inhibitors have become important tools to probe HIE-1 regulation. Salceda and Caro found that inhibition of the ubiquitin-proteasome system with lactacystin (23) caused HIE-lct accumulation, indicating that HIE-lct protein is rapidly degraded by the ubiquitin-proteasome under normoxic conditions and that redox-induced biochemical modification mediates the changes in HIE-lct protein stability... 

In view of the chemical structure of MDMO-PPV, it is expected that this polymer is very sensitive to solar light. This is attested by several studies that clearly show that oxygen-dependent degradation of the polymer plays a significant role in the failure of devices based on MDMO-PPV [15-18]. Carbonyl defects were shown to have a major influence on devices like PLEDS and the increase of carbonyl defects was correlated to a dramatic reduction of the photoluminescence of the polymer [19,20], Understandings about the origin and the formation of these defects seem relevant in order to improve the stability of the devices based on this kind of polymer. 

L.E. Huang, J. Gu, M. Schau, H.F. Bunn (1998). Regulation of hypoxia-inducible factor la is mediated by an oxygen dependent degradation domain via the ubiquitin proteasome pathway. Proc. Natl Acad. ScL U.S.A., 95, 7987-7992. 

HIF-1 is a heterodimeric transcription factor composed of an alpha subunit (HIF-la) and a constitutively expressed beta subunit (HIF-1 p) [74]. HIF-1 activity is mainly dependent on the level of HIF-la protein [74, 75]. Under hypoxic conditions, HIF-la interacts with HIF-1 p and functions as a transcription factor. Under normoxic conditions, the oxygen-dependent degradation (ODD) domain of HIF-la is hydroxylated by prolyl hydroxylases (PHDs) and ubiquitinated by the von Hippel-Lindau (VHL) tumor suppressor protein-containing E3 ubiquitin ligase, resulting in rapid degradation of the HIF-la protein [76, 77]. 

Harada H, Hiraoka M, Kizaka-Kondoh S. Antitumor effect of TAT-oxygen-dependent degradation-caspase-3 fusion protein specifically stabilized and activated in hypoxic tumor cells. Cancer Res 2002 62 2013-2018. 

Figure 1 structure of the mouse gene encoding HIF-la (flifla) and the mature HIF-1 mRNA. Domains hHLH, basic-helix-loop-helix PAS, Per-Amt-Sim N-TA, N-terminal rrani-activation ODD, oxygen-dependent degradation C-TA, C-terminal TA. 

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