Glycogen synthase kinase 3 (GSK3), a constitutively acting multi-functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. These diverse multiple functions attributed to GSK3 can be explained by variety of substrates like glycogen synthase, t protein and b catenin that are phosphorylated leading to their inactivation. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin-mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity. The primary concern is developing inhibitors of GSK3 that are anti-diabetic but do not lead to up-regulation of oncogenes. The focus of this review is the recent advances and the challenges surrounding GSK3 as an anti-diabetic therapeutic target.

P.Chambon and R.Losson contributed equally to this workThe nuclear receptor-binding SET domain-containing protein (NSD1) belongs to an emerging family of proteins, which have all been implicated in human malignancy. To gain insight into the biological functions of NSD1, we have generated NSD1-de®cient mice by gene disruption. Homozygous mutant NSD1 embryos, which initiate mesoderm formation, display a high incidence of apoptosis and fail to complete gastrulation, indicating that NSD1 is a developmental regulatory protein that exerts function(s) essential for early post-implantation development. We have also examined the enzymatic potential of NSD1 and found that its SET domain possesses intrinsic histone methyltransferase activity with speci®city for Lys36 of histone H3 (H3-K36) and Lys20 of histone H4 (H4-K20).

Women constitute approximately 45% of the postdoctoral fellows in the biomedical sciences at universities and research institutions in the USA, but a much lower percentage of women hold faculty positions. In the US National Institutes of Health (NIH; Bethesda, MD) Intramural Research Program, for example, women make up only 29% of the tenure-track investigators and hold just 19% of the tenured senior investigator appointments. A similar disparity between the ratio of men and women in independent faculty positions exists in most academic institutions across the USA (Nelson, 2005; NSF, 2004 NSF, , 2006, and statistics from Europe show a similar trend of women disappearing from the higher echelons of academia (EC, 2006).The transition from postdoctoral fellow to faculty is a period during which a worrying number of women leave academic research. Several recent surveys have tried to identify factors that lead to the attrition of women from the life sciences and engineering (University of California, 2005; Princeton University, 2003; University of Michigan, 2004;Baltimore et al, 2005), but these have not addressed the important question: why are female postdoctoral fellows falling off the academic bandwagon in greater numbers than male postdoctoral fellows?During the past ten years, the percentage of women in tenured positions at the NIH increased slightly, from 18% to 19%, but the percentage of women in tenuretrack positions remained unchanged. These facts led to the establishment of the Second Task Force on the Status of NIH Intramural Women Scientists. As part of this task force, the Postdoctoral Fellows Subcommittee set out to identify factors that might influence the decision of female postdoctoral fellows to pursue a position as a principal or independent investigator (PI). As several studies have previously identified family demands and self-confidence as factors that generally draw women away from the workforce at large (Kaplan & Granrose, 1993; Sears, 2003;Mason & Goulden, 2004;Hoonakker & Schoepke, 2005), our survey included questions to determine how these and other factors affect young female scientists in their career choices at the postdoc to PI transition.More than 1,300 intramural postdoctoral fellows at the NIH-from a total of 2,437-took part in a web-based survey. Of these, 43% were women and 57% were men, which reflects the nationwide gender distribution of postdoctoral fellows in the biological sciences (Nelson, 2005; NSF, 2004 NSF, , 2006. Although the age distribution was the same for men and women in this sample group, there was a clear difference between the percentage of men (44%) and the percentage of women (33.6%) with children (Table 1). Women with children are underrepresented in the postdoctoral workforce.The substantially lower percentage of female PIs could simply indicate that women are less likely to consider or pursue a career as a PI; therefore, we asked NIH fellows what type of career they were considering. More than two-thirds of the men but one-half of the women answered t...

Progesterone receptor (PR), a member of the nuclear receptor superfamily, is a key regulator of several processes in reproductive function. We have studied the dynamics of the interaction of PR with a natural target promoter in living cells through the use of fluorescence recovery after photobleaching (FRAP) analysis and also have characterized the dynamics of the interaction of PR with the mouse mammary tumor virus (MMTV) promoter reconstituted into chromatin in vitro. In photobleaching experiments, PR in the presence of the agonist R5020 exhibits rapid exchange with the MMTV promoter in living cells. Two PR antagonists, RU486 and ZK98299, have opposite effects on receptor dynamics in vivo. In the presence of RU486, PR binds to the promoter and is exchanged more slowly than the agonist-activated receptor. In contrast, PR bound to ZK98299 is not localized to the promoter and exhibits higher mobility in the nucleoplasm than the agonist-bound receptor. Significantly, PR bound to R5020 or RU486 can recruit the SWI/SNF chromatin remodeling complex to the promoter, but PR activated with ZK98299 cannot. Furthermore, we found ligand-specific active displacement of PR from the MMTV promoter during chromatin remodeling in vitro and conclude that the interaction of PR with chromatin is highly dynamic both in vivo and in vitro. We propose that factor displacement during chromatin remodeling is an important component of receptor mobility and that ligandspecific interactions with remodeling complexes can strongly influence receptor nuclear dynamics and rates of exchange with chromatin in living cells.