Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor ␣ subunits (HIF-1␣ and HIF-2␣), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1␣ and HIF-2␣ in RCC and non-RCC cells. We demonstrate common patterns of HIF-␣ isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF-␣ isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2␣ suppressing HIF-1␣ and vice-versa. In VHL-defective RCC cells, we demonstrate that the protumorigenic genes encoding cyclin D1, transforming growth factor alpha, and vascular endothelial growth factor respond specifically to HIF-2␣ and that the proapoptotic gene encoding BNip3 responds positively to HIF-1␣ and negatively to HIF-2␣, indicating that HIF-1␣ and HIF-2␣ have contrasting properties in the biology of RCC. In keeping with this, HIF-␣ isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1␣ retarding and HIF-2␣ enhancing tumor growth. These findings indicate that therapeutic approaches to targeting of the HIF system, at least in this setting, will need to take account of HIF isoform-specific functions.
The Central Asian Orogenic Belt records the accretion and convergence of three collage systems that were finally rotated into two major oroclines. The Mongolia collage system was a long, N–S-oriented composite ribbon that was rotated to its current orientation when the Mongol-Okhotsk orocline was formed. The components of the Kazakhstan collage system were welded together into a long, single composite arc that was bent to form the Kazakhstan orocline. The cratons of Tarim and North China were united and sutured by the Beishan orogen, which terminated with formation of the Solonker suture in northern China. All components of the three collage systems were generated by the Neoproterozoic and were amalgamated in the Permo-Triassic. The Central Asian Orogenic Belt evolved by multiple convergence and accretion of many orogenic components during multiple phases of amalgamation, followed by two phases of orocline rotation.
An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via β-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo.
Bloom's syndrome (BS) is an autosomal recessive disorder associated with dwarfism, immunodeficiency, reduced fertility, and elevated levels of many types of cancer. BS cells show marked genomic instability; in particular, hyperrecombination between sister chromatids and homologous chromosomes. This instability is thought to result from defective processing of DNA replication intermediates. The gene mutated in BS, BLM, encodes a member of the RecQ family of DExH box DNA helicases, which also includes the Werner's syndrome gene product. We have investigated the mechanism by which BLM suppresses hyperrecombination. Here, we show that BLM selectively binds Holliday junctions in vitro and acts on recombination intermediates containing a Holliday junction to promote ATP-dependent branch migration. We present a model in which BLM disrupts potentially recombinogenic molecules that arise at sites of stalled replication forks. Our results have implications for the role of BLM as an anti-recombinase in the suppression of tumorigenesis.
The cell surface receptor, low-density lipoprotein receptorrelated protein 5 (LRP5) is a key regulator of bone mass. Lossof-function mutations in LRP5 cause the human skeletal disease osteoporosis-pseudoglioma syndrome, an autosomal recessive disorder characterized by severely reduced bone mass and strength. We investigated the role of LRP5 on bone strength using mice engineered with a loss-of-function mutation in the gene. We then tested whether the osteogenic response to mechanical loading was affected by the loss of Lrp5 signaling. In addition to studies in humans, mice have been created with loss-of-function mutations in the mouse ortholog of LRP5, called Lrp5 (9 -11). These mice recapitulate the clinical features observed in OPPG patients, suggesting that the mouse is a useful animal model for delineating the role of Lrp5 in the mammalian skeleton (9 -11). Additionally, transgenic mice that overexpress wild-type Lrp5 or a high bone mass causing missense allele of LRP5 (G171V) under control of the type I collagen promoter, have increased bone mass and skeletal strength (12). Taken together, these data indicate that LRP5 has an important role in determining skeletal mass, strength, and function.
Lrp5-null (Lrp5Although loss-of-function mutations in LRP5 impart clear deficiencies on the skeleton, it is unclear how LRP5 participates in the modulation of bone mass. The striking similarity between * This work was supported by National Institutes of Health Grants AR046530 (to C. H. T.) and AR053237 (to A. G. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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