Search

Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are α-ketoglutarate (αKG)-dependent dioxygenases that function as cellular oxygen sensors. However, PHD activity also depends on factors other than oxygen, especially αKG, a key metabolic compound closely linked to amino-acid metabolism. We examined the connection between amino-acid availability and PHD activity. We found that amino-acid starvation leads to αKG depletion and to PHD inactivation but not to HIF stabilization. Furthermore, pharmacologic or genetic inhibition of PHDs induced autophagy and prevented mammalian target of rapamycin complex 1 (mTORC1) activation by amino acids in a HIF-independent manner. Therefore, PHDs sense not only oxygen but also respond to amino acids, constituting a broad intracellular nutrient-sensing network. [ABSTRACT FROM AUTHOR]

Release from growth factor dependence and acquisition of signalling pathway addiction are critical steps in oncogenesis. To identify genes required on mammalian target of rapamycin (mTOR) addiction, we performed a genome-wide short hairpin RNA screen on a v-H-ras-transformed Pten-deficient cell line that displayed two alternative growth modes, interleukin (IL)-3-independent/mTOR-addicted proliferation (transformed growth mode) and IL-3-dependent/mTOR-non-addicted proliferation (normal growth mode). We screened for genes required only in the absence of IL-3 and thus specifically for the transformed growth mode. The top 800 hits from this conditional lethal screen were analyzed in silico and 235 hits were subsequently rescreened in two additional Pten-deficient cell lines to generate a core set of 47 genes. Hits included genes encoding mTOR and the mTOR complex 2 (mTORC2) component rictor and several genes encoding mitochondrial functions including components of the respiratory chain, adenosine triphosphate synthase, the mitochondrial ribosome and mitochondrial fission factor. Small interfering RNA knockdown against a sizeable fraction of these genes triggered apoptosis in human cancer cell lines but not in normal fibroblasts. We conclude that mTORC2-addicted cells require mitochondrial functions that may be novel drug targets in human cancer. [ABSTRACT FROM AUTHOR]

Background: This study updates prevalence estimates of gambling-related disorders in the United States and Canada, identifies differences in prevalence estimates among population segments, and identifies changes in prevalence over the past 25 years., Method: A meta-analytic strategy guided the synthesis of 180 estimates derived from 146 prevalence studies., Results: Prevalence estimates among adolescent samples were significantly higher than estimates among adult samples for both clinical (level 3) and sub-clinical (level 2) measures of disordered gambling within both lifetime and past-year time frames. Among adults, level 3 prevalence estimates continue to increase significantly., Conclusions: Membership in youth, treatment, and prison population segments is significantly associated with experiencing gambling-related disorders. Understanding sub-clinical gamblers provides a meaningful opportunity to lower the public health burden associated with gambling disorders. Prospective studies of incidence are necessary to determine whether the prevalence of disordered gambling continues to increase among the adult general population and how adolescent gambling experiences change as this cohort ages.