Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin.

Renal peritubular interstitial fibroblast-like cells are critical for adult erythropoiesis, as they are the main source of erythropoietin (EPO). Hypoxia-inducible factor 2 (HIF-2) controls EPO synthesis in the kidney and liver and is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3, which function as cellular oxygen sensors. Renal interstitial cells with EPO-producing capacity are poorly characterized, and the role of the PHD/HIF-2 axis in renal EPO-producing cell (REPC) plasticity is unclear.

Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin.

The adult kidney plays a central role in erythropoiesis and is the main source of erythropoietin (EPO), an oxygen-sensitive glycoprotein that is essential for red blood cell production. Decreases of renal pO2 promote hypoxia-inducible factor 2-mediated (HIF-2-mediated) induction of EPO in peritubular interstitial fibroblast-like cells, which serve as the cellular site of EPO synthesis in the kidney. It is not clear whether HIF signaling in other renal cell types also contributes to the regulation of EPO production.

Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis.

Iron demand in bone marrow increases when erythropoiesis is stimulated by hypoxia via increased erythropoietin (EPO) synthesis in kidney and liver. Hepcidin, a small polypeptide produced by hepatocytes, plays a central role in regulating iron uptake by promoting internalization and degradation of ferroportin, the only known cellular iron exporter. Hypoxia suppresses hepcidin, thereby enhancing intestinal iron uptake and release from internal stores.

Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury.

Renal fibrosis and inflammation are associated with hypoxia, and tissue pO(2) plays a central role in modulating the progression of chronic kidney disease. Key mediators of cellular adaptation to hypoxia are hypoxia-inducible factor (HIF)-1 and -2. In the kidney, they are expressed in a cell type-specific manner; to what degree activation of each homolog modulates renal fibrogenesis and inflammation has not been established.

Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia.

The kidney is the main physiologic source of erythropoietin (EPO) in the adult and responds to decreases in tissue oxygenation with increased EPO production. Although studies in mice with liver-specific or global gene inactivation have shown that hypoxia-inducible factor 2 (Hif-2) plays a major role in the regulation of Epo during infancy and in the adult, respectively, the contribution of renal HIF-2 signaling to systemic EPO homeostasis and the role of extrarenal HIF-2 in erythropoiesis, in the absence of kidney EPO, have not been examined directly. Here, we used Cre-loxP recombination to ablate Hif-2α in the kidney, whereas Hif-2-mediated hypoxia responses in the liver and other Epo-producing tissues remained intact.

Nek2 targets the mitotic checkpoint proteins Mad2 and Cdc20: a mechanism for aneuploidy in cancer.

In mitosis, the duplicated chromosomes are separated and equally distributed to progeny cells under the guidance of the spindle, a dynamic microtubule network. Previous studies revealed a mitotic checkpoint that prevents segregation of the chromosomes until all of the chromosomes are properly attached to microtubules through the kinetochores. A variety of kinetochore-localized proteins, including Mad2 and Cdc20, have been implicated in controlling the mitotic checkpoint.

Hypoxia-inducible factor 2 regulates hepatic lipid metabolism.

In mammals, the liver integrates nutrient uptake and delivery of carbohydrates and lipids to peripheral tissues to control overall energy balance. Hepatocytes maintain metabolic homeostasis by coordinating gene expression programs in response to dietary and systemic signals. Hepatic tissue oxygenation is an important systemic signal that contributes to normal hepatocyte function as well as disease.

Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo.

Erythropoiesis is critically dependent on erythropoietin (EPO), a glycoprotein hormone that is regulated by hypoxia-inducible factor (HIF). Hepatocytes are the primary source of extrarenal EPO in the adult and express HIF-1 and HIF-2, whose roles in the hypoxic induction of EPO remain controversial. In order to define the role of HIF-1 and HIF-2 in the regulation of hepatic EPO expression, we have generated mice with conditional inactivation of Hif-1alpha and/or Hif-2alpha (Epas1) in hepatocytes.

Characterization of Su48, a centrosome protein essential for cell division.

The centrosome functions as the major microtubule-organizing center and plays a vital role in guiding chromosome segregation during mitosis. Centrosome abnormalities are frequently seen in a variety of cancers, suggesting that dysfunction of this organelle may contribute to malignant transformation. In our efforts to identify the protein components of the centrosome and to understand the structure features involved in the assembly and functions of this organelle, we cloned and characterized a centrosome-associated protein called Su48.

UXT is a novel centrosomal protein essential for cell viability.

Ubiquitously expressed transcript (UXT) is a prefoldinlike protein that has been suggested to be involved in human tumorigenesis. Here, we have found that UXT is overexpressed in a number of human tumor tissues but not in the matching normal tissues. We demonstrate that UXT is located in human centrosomes and is associated with gamma-tubulin.

The centrosome in normal and transformed cells.

The centrosome is a unique organelle that functions as the microtubule organizing center in most animal cells. During cell division, the centrosomes form the poles of the bipolar mitotic spindle. In addition, the centrosomes are also needed for cytokinesis.

Molecular Cloning and Sequence Analysis of cDNA Encoding Acutolysin C, a Hemorrhagic Metalloproteinase, from Agkistrodon acutus.

A full-length cDNA of 1 650 bp was amplified from the snake venom gland cDNA library of Agkistrodon acutus. Analysis of the nucleotide sequence indicated that the amplified cDNA contained a complete open reading frame encoding 417 amino acid residues including signal peptide sequence, zymogen sequence and proteinase domain. The zymogen sequence contained CGVT motif that was highly conserved in almost all venom metalloproteinases.

Purification and Characterization of a Platelet Agglutinating Inhibiting Protein (Agkisacutacin) from Agkistrodon acutus Venom.

A platelet agglutinating inhibiting protein (agkisacutacin) was isolated from the venom of Agkistrodon acutus by DEAE Sepharose Fast Flow and size exclusion chromatography. The purified product was a 29 kD protein composed of two disulfide bond-linked polypeptide chains of molecular weight of 14 kD, 15 kD, respectively. It completely inhibited ristocetin-induced platelet agglutination with an IC(50) value of 18.

Disabling receptor ensembles with rationally designed interface peptidomimetics.

Members of the erbB family receptor tyrosine kinases (erbB1, erbB2, erbB3, and erbB4) are overexpressed in a variety of human cancers and represent important targets for the structure-based drug design. Homo- and heterodimerization (oligomerization) of the erbB receptors are known to be critical events for receptor signaling. To block receptor self-associations, we have designed a series of peptides derived from potential dimerization surfaces in the extracellular subdomain IV of the erbB receptors (erbB peptides).