In this paper we suggest that 2011–2012 may mark a paradigm shift in dominant constructions of ‘foreign aid’ and a substantive shift of power within the architecture of global development governance. We evaluate critically the emergence and central principles of the ‘aid effectiveness paradigm’ over the last 10–15 years, and the various internal and external pressures that have mounted around it. We then discuss the Fourth High Level Forum on Aid Effectiveness, a global conference which was held in Busan, South Korea in 2011, which we suggest can be seen as a pivot point in the emergence of a new ‘development effectiveness’ paradigm. Among other things, this elevates the role of the private sector and re‐centres economic growth and enhanced productivity to the core of mainstream ‘development’ thinking. At the same time, the emerging aid architecture aims to enrol more fully the ‘(re‐)emerging’ donors and development partners, and is likely to involve more differentiated commitments to global aid targets and renegotiated ‘norms’. This paper provides a commentary on the debates, omissions and achievements of the Busan High Level Forum, with the wider aim of providing critical insights into the current state of flux around foreign aid norms, institutions and governance.

Histone methylation is crucial for transcriptional regulation and chromatin remodeling. It has been suggested that the SET domain containing protein RE-IIBP (interleukin-5 [IL-5] response element II binding protein) may perform a function in the carcinogenesis of certain tumor types, including myeloma. However, the pathogenic role of RE-IIBP in these diseases remains to be clearly elucidated. In this study, we have conducted an investigation into the relationship between the histone-methylating activity of RE-IIBP and transcriptional regulation. Here, we report that RE-IIBP is up-regulated in the blood cells of leukemia patients, and we characterized the histone H3 lysine 27 (H3-K27) methyltransferase activity of RE-IIBP. Point mutant analysis revealed that SET domain cysteine 483 and arginine 477 are critical residues for the histone methyltransferase (HMTase) activity of RE-IIBP. RE-IIBP also represses basal transcription via histone deacetylase (HDAC) recruitment, which may be mediated by H3-K27 methylation. In the chromatin immunoprecipitation assays, we showed that RE-IIBP overexpression induces histone H3-K27 methylation, HDAC recruitment, and histone H3 hypoacetylation on the IL-5 promoter and represses expression. Conversely, short hairpin RNA-mediated knockdown of RE-IIBP reduces histone H3-K27 methylation and HDAC occupancy around the IL-5 promoter. These data illustrate the important regulatory role of RE-IIBP in transcriptional regulation, thereby pointing to the important role of HMTase activity in carcinogenesis.In eukaryotes, chromatin structure is modulated via the various posttranslational modifications of histone NH 2 -terminal tails. An accumulating body of evidence suggests that these histone modifications may play a role in a host of chromatin remodeling-associated processes, including replication, transcription, and DNA repair (7). One of the covalent modifications, histone lysine methylation, is facilitated by SET domainharboring proteins and has been found to have important roles in chromatin remodeling and regulating gene expression (20). The SET domain-harboring proteins are a large family which was identified initially in three Drosophila proteins: Suppressor of variegation [Sur(var)3-9], Enhancer of zeste [E(z)], and Trithorax. Over 200 SET domain-harboring genes have been predicted to exist in various species, suggesting that this domain is highly conserved and that it may play critical roles in certain cellular functions. Within the last few decades, an increasing amount of evidence has been generated to support the notion that aberrant transcriptional regulation contributes to the development of human cancers. In fact, transcription regulatory proteins are often identified in oncogenic chromosomal rearrangements and have been shown to be overexpressed in a variety of malignancies. It has also been suggested that malfunctions in histone methylation may be linked to cancer as well as other diseases. When growth-regulatory genes are methylated in an aberrant manner, the relevant genes...

CYP3A4 is a dominant human liver cytochrome P450 enzyme engaged in the metabolism and disposition of >50% of clinically relevant drugs and held responsible for many adverse drugdrug interactions. CYP3A4 and its mammalian liver CYP3A orthologs are endoplasmic reticulum (ER)-anchored monotopic proteins that undergo ubiquitin (Ub)-dependent proteasomal degradation (UPD) in an ER-associated degradation (ERAD) process. These integral ER proteins are ubiquitinated in vivo, and in vitro studies have identified the ER-integral gp78 and the cytosolic co-chaperone, CHIP (C terminus of Hsp70-interacting protein), as the relevant E3 Ub-ligases, along with their cognate E2 Ub-conjugating enzymes UBC7 and UbcH5a, respectively. Using lentiviral shRNA templates targeted against each of these Ub-ligases, we now document that both E3s are indeed physiologically involved in CYP3A ERAD/UPD in cultured rat hepatocytes. Accordingly, specific RNAi resulted in ≈80% knockdown of each hepatic Ub-ligase, with a corresponding ≈2.5-fold CYP3A stabilization. Surprisingly, however, such stabilization resulted in increased levels of functionally active CYP3A, thereby challenging the previous notion that E3 recognition and subsequent ERAD of CYP3A proteins required ab initio their structural and/or functional inactivation. Furthermore, coexpression in HepG2 cells of both CYP3A4 and gp78, but not its functionally inactive RING-finger mutant, resulted in enhanced CYP3A4 loss greater than that in corresponding cells expressing only CYP3A4. Stabilization of a functionally active CYP3A after RNAi knockdown of either of the E3s, coupled with the increased CYP3A4 loss on gp78 or CHIP coexpression, suggests that ERAD-associated E3 Ub-ligases can influence clinically relevant drug metabolism by effectively regulating the physiological CYP3A content and consequently its function.The CYP3A subfamily of hepatic cytochrome P450 hemoproteins includes CYP3A4, the dominant human liver P450 enzyme responsible for the metabolism of more than 50% of clinically relevant drugs and other xenobiotics (1). The CYPs 3A, 2 in common with many hepatic P450s, are excellent examples of integral endoplasmic reticulum (ER) membrane-anchored monotopic proteins, with their N termini embedded in the ER and their catalytic domains exposed to the cytosol. Using various in vivo and in vitro reconstituted eukaryotic systems, we have shown that both native 3 and structurally inactivated CYPs 3A incur ubiquitin (Ub)-dependent proteasomal degradation (UPD), in a typical ER-associated degradation (ERAD) process involving phosphorylation, ubiquitination, ER membrane extraction into the cytosol, and subsequent degradation by the 26S proteasome (2-13). Indeed mechanism-based CYP3A inactivation often results in active site structural lesions within their cytosolic domain (2, 6, 7), thereby qualifying these proteins as bona fide ERAD-C substrates.The pathways of P450 degradation appear to be highly conserved in all eukaryotes from yeast to man (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22...

The dynamic exchange of histone lysine methylation status by histone methyltransferases and demethylases has been previously implicated as an important factor in chromatin structure and transcriptional regulation. Using immunoaffinity TAP analysis, we purified the WHISTLE-interacting protein complexes, which include the heat shock protein HSP90α and the jumonji C-domain harboring the histone demethylase JMJD1C. In this study, we demonstrate that JMJD1C specifically demethylates histone H3K9 mono- and di-methylation, and mediates transcriptional activation. We also provide evidence suggesting that both WHISTLE and JMJD1C performs functions in the development of mouse testes by regulating the expression of the steroidogenesis marker, p450c17, via SF-1-mediated transcription. Furthermore, we demonstrate that WHISTLE is recruited to the p450c17 promoter via SF-1 and represses the transcription of prepubertal stages of steroidogenesis, after which JMJD1C replaces WHISTLE and activates the expression of target genes via SF-1-mediated interactions. Our results demonstrate that the histone methylation balance mediated by HMTase WHISTLE and demethylase JMJD1C perform a transcriptional regulatory function in mouse testis development.