Hypoxia inducible factor (HIF) is regulated by dual pathways involving oxygen-dependent prolyl and asparaginyl hydroxylation of its α-subunits. Prolyl hydroxylation at two sites within a central degradation domain promotes association of HIF-α with the von Hippel-Lindau ubiquitin E3 ligase and destruction by the ubiquitin-proteasome pathways. Asparaginyl hydroxylation blocks the recruitment of p300/CBP co-activators to a C-terminal activation domain in HIF-α. These hydroxylations are catalyzed by members of the Fe(II) and 2-oxoglutarate (2-OG) oxygenase family. Activity of the enzymes is suppressed by hypoxia, increasing both the abundance and activity of the HIF transcriptional complex. We have used hydroxy residue-specific antibodies to compare and contrast the regulation of each site of prolyl hydroxylation (Pro402, Pro564) with that of asparaginyl hydroxylation (Asn803) in human HIF-1α. Our findings reveal striking differences in the sensitivity of these hydroxylations to hypoxia and to different inhibitor types of 2-OG oxygenases. Hydroxylation at the three sites in endogenous human HIF-1α proteins was suppressed by hypoxia in the order Pro402 > Pro564 > Asn803. In contrast to some predictions from in vitro studies, prolyl hydroxylation was substantially more sensitive than asparaginyl hydroxylation to inhibition by iron chelators and transition metal ions; studies of a range of different small molecule 2-OG analogues demonstrated the feasibility of selectively inhibiting either prolyl or asparaginyl hydroxylation within cells.

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Seven key community resources (physical, economic, biological, organisational, social, cultural and aesthetic resources) were studied in each of 22 common local urban townscape areas in 11 cities in the Baltic Sea region. A method was developed for multi-dimensional assessment of the sustainability status of the local communities according to the United Nations Habitat agenda. From an analysis of strong and weak points of the seven resources, a contextual micro-comprehensive plan for sustainable community development was outlined for each local area, comprising three components: universal, townscape-type-specific and place-specific strategies. The research also revealed unique key drivers for change for each area – either a specific problem or a vision for change. By addressing the key drivers, it is suggested that sustainable community development could be more efficiently introduced and implemented.

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