07 September 2008
Natural selection of FLT1 alleles and their association with malaria resistance in utero
Placental malaria (PM) caused by Plasmodium falciparum contributes significantly to infant mortality in sub-Saharan Africa and is associated with pregnancy loss. We hypothesized that fetal genes that modify PM would be associated with fetal fitness. During PM, placental trophoblasts produce soluble fms-like tyrosine kinase 1 (sFlt1), also known as soluble VEGF receptor 1, an angiogenesis inhibitor associated with preeclampsia. Here we present a study examining the genotype of the fms-related tyrosine kinase 1 (FLT1) 3′ UTR in Tanzanian mother–infant pairs. First-time mothers suffer the most PM, and newborn FLT1 genotype distribution differed by birth order, with newborns of first-time mothers outside of Hardy–Weinberg equilibrium (HWE) during peak PM season. Among first-time but not other mothers, maternal FLT1 genotype was associated with a history of prior pregnancy loss. During PM, newborn FLT1 genotype was associated with low birth weight and placental inflammatory gene expression. FLT1 genotype was also associated with Flt1 levels among study subjects and in vitro. Thus, FLT1 variants confer fetal fitness in utero and are associated with the maternal immune response during PM. This indicates that FLT1 is under natural selection in a malaria endemic area and that human exposure to malaria can influence the evolutionary genetics of the maternal-fetal relationship.
PNAS published September 8, 2008, doi:10.1073/pnas.0803657105
PNAS published September 8, 2008, doi:10.1073/pnas.0803657105
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Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: The Generation R study.
Concern about potential health impacts of low-level exposures to organophosphorus (OP) pesticides, bisphenol A (BPA), and phthalates among the general population is increasing. We measured levels of six dialkyl phosphate (DAP) metabolites of OP pesticides, a chlorpyrifos-specific metabolite (3,5,6-trichloro-2-pyridinol, TCPy), BPA, and 14 phthalate metabolites in urine samples of 100 pregnant women from the Generation R study, the Netherlands. The unadjusted and creatinine-adjusted concentrations were reported, and compared to National Health and Nutrition Examination Survey and other studies. In general, these metabolites were detectable in the urine of the women from the Generation R study and compared with other groups, they had relatively high-level exposures to OP pesticides and several phthalates but similar exposure to BPA. The median concentrations of total dimethyl (DM) metabolites was 264.0nmol/g creatinine (Cr) and of total DAP was 316.0nmol/g Cr. The median concentration of mono-ethyl phthalate (MEP) was 222.0mug/g Cr; the median concentrations of mono-isobutyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were above 50mug/g Cr. The median concentrations of the three secondary metabolites of di-2-ethylhexyl phthalate (DEHP) were greater than 20mug/g Cr. The data indicate that the Generation R study population provides a wide distribution of selected environmental exposures. Reasons for the relatively high levels and possible health effects need investigation.
Environ Res. 2008 Sep 4. [Epub ahead of print]
Environ Res. 2008 Sep 4. [Epub ahead of print]
Bisphenol A prevents the synaptogenic response to estradiol in hippocampus and prefrontal cortex of ovariectomized nonhuman primates.
Exposure measurements from several countries indicate that humans are routinely exposed to low levels of bisphenol A (BPA), a synthetic xenoestrogen widely used in the production of polycarbonate plastics. There is considerable debate about whether this exposure represents an environmental risk, based on reports that BPA interferes with the development of many organs and that it may alter cognitive functions and mood. Consistent with these reports, we have previously demonstrated that BPA antagonizes spine synapse formation induced by estrogens and testosterone in limbic brain areas of gonadectomized female and male rats. An important limitation of these studies, however, is that they were based on rodent animal models, which may not be representative of the effects of human BPA exposure. To address this issue, we examined the influence of continuous BPA administration, at a daily dose equal to the current U.S. Environmental Protection Agency's reference safe daily limit, on estradiol-induced spine synapse formation in the hippocampus and prefrontal cortex of a nonhuman primate model. Our data indicate that even at this relatively low exposure level, BPA completely abolishes the synaptogenic response to estradiol. Because remodeling of spine synapses may play a critical role in cognition and mood, the ability of BPA to interfere with spine synapse formation has profound implications. This study is the first to demonstrate an adverse effect of BPA on the brain in a nonhuman primate model and further amplifies concerns about the widespread use of BPA in medical equipment, and in food preparation and storage.
Proc Natl Acad Sci U S A. 2008 Sep 3. [Epub ahead of print]
Proc Natl Acad Sci U S A. 2008 Sep 3. [Epub ahead of print]
Global Sequencing of Proteolytic Cleavage Sites in Apoptosis by Specific Labeling of Protein N Termini
The nearly 600 proteases in the human genome regulate a diversity of biological processes, including programmed cell death. Comprehensive characterization of protease signaling in complex biological samples is limited by available proteomic methods. We have developed a general approach for global identification of proteolytic cleavage sites using an engineered enzyme to selectively biotinylate free protein N termini for positive enrichment of corresponding N-terminal peptides. Using this method to study apoptosis, we have sequenced 333 caspase-like cleavage sites distributed among 292 protein substrates. These sites are generally not predicted by in vitro caspase substrate specificity but can be used to predict other physiological caspase cleavage sites. Structural bioinformatic studies show that caspase cleavage sites often appear in surface-accessible loops and even occasionally in helical regions. Strikingly, we also find that a disproportionate number of caspase substrates physically interact, suggesting that these dimeric proteases target protein complexes and networks to elicit apoptosis.
Cell, Volume 134, Issue 5, 5 September 2008, Pages 866-876
Cell, Volume 134, Issue 5, 5 September 2008, Pages 866-876
UBXD7 Binds Multiple Ubiquitin Ligases and Implicates p97 in HIF1α Turnover
p97 is an ATP-dependent chaperone that plays an important role in endoplasmic reticulum-associated degradation but whose connections to turnover of soluble proteins remain sparse. Binding of p97 to substrates is mediated by cofactors that contain ubiquitin-binding domains. We employed “network proteomics” to show that p97 assembles with all of the 13 mammalian UBX-domain proteins. The UBX proteins that bind ubiquitin conjugates also interact with dozens of E3 ubiquitin ligases, only one of which had been previously linked to p97. In particular, UBXD7 links p97 to the ubiquitin ligase CUL2/VHL and its substrate hypoxia-inducible factor 1α (HIF1&alpha
. Depletion of p97 leads to accumulation of endogenous HIF1α and increased expression of a HIF1α target gene. The large number of ubiquitin ligases found associated with UBX proteins suggests that p97 plays a far broader role than previously anticipated in the global regulation of protein turnover.
Cell, Vol 134, 804-816, 05 September 2008
. Depletion of p97 leads to accumulation of endogenous HIF1α and increased expression of a HIF1α target gene. The large number of ubiquitin ligases found associated with UBX proteins suggests that p97 plays a far broader role than previously anticipated in the global regulation of protein turnover.Cell, Vol 134, 804-816, 05 September 2008
Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase αC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling.
Cell, Vol 134, 793-803, 05 September 2008
Cell, Vol 134, 793-803, 05 September 2008
Human-Specific Gain of Function in a Developmental Enhancer
Changes in gene regulation are thought to have contributed to the evolution of human development. However, in vivo evidence for uniquely human developmental regulatory function has remained elusive. In transgenic mice, a conserved noncoding sequence (HACNS1) that evolved extremely rapidly in humans acted as an enhancer of gene expression that has gained a strong limb expression domain relative to the orthologous elements from chimpanzee and rhesus macaque. This gain of function was consistent across two developmental stages in the mouse and included the presumptive anterior wrist and proximal thumb. In vivo analyses with synthetic enhancers, in which human-specific substitutions were introduced into the chimpanzee enhancer sequence or reverted in the human enhancer to the ancestral state, indicated that 13 substitutions clustered in an 81–base pair module otherwise highly constrained among terrestrial vertebrates were sufficient to confer the human-specific limb expression domain.
Science 5 September 2008: Vol. 321. no. 5894, pp. 1346 - 1350
DOI: 10.1126/science.1159974
Science 5 September 2008: Vol. 321. no. 5894, pp. 1346 - 1350
DOI: 10.1126/science.1159974
Calcification of Multipotent Prostate Tumor Endothelium
Solid tumors require new blood vessels for growth and metastasis, yet the biology of tumor-specific endothelial cells is poorly understood. We have isolated tumor endothelial cells from mice that spontaneously develop prostate tumors. Clonal populations of tumor endothelial cells expressed hematopoietic and mesenchymal stem cell markers and differentiated to form cartilage- and bone-like tissues. Chondrogenic differentiation was accompanied by an upregulation of cartilage-specific col2a1 and sox9, whereas osteocalcin and the metastasis marker osteopontin were upregulated during osteogenic differentiation. In human and mouse prostate tumors, ectopic vascular calcification was predominately luminal and colocalized with the endothelial marker CD31. Thus, prostate tumor endothelial cells are atypically multipotent and can undergo a mesenchymal-like transition.
Cancer Cell, Vol 14, 201-211, 09 September 2008
Cancer Cell, Vol 14, 201-211, 09 September 2008
Rapid Chemotherapy-Induced Acute Endothelial Progenitor Cell Mobilization: Implications for Antiangiogenic Drugs as Chemosensitizing Agents
Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g., paclitaxel, can rapidly induce proangiogenic bone marrow-derived circulating endothelial progenitor (CEP) mobilization and subsequent tumor homing, whereas others, e.g., gemcitabine, do not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1α and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or paclitaxel treatment in CEP-deficient Id mutant mice, both of which resulted in enhanced antitumor effects mediated by paclitaxel, but not by gemcitabine.
Cancer Cell, Volume 14, Issue 3, 9 September 2008, Pages 263-273
Cancer Cell, Volume 14, Issue 3, 9 September 2008, Pages 263-273