HIF and c-Myc: Sibling Rivals for Control of Cancer Cell Metabolism and Proliferation

O2 deprivation (hypoxia) and cellular proliferation engage opposite cellular pathways, yet often coexist during tumor growth. The ability of cells to grow during hypoxia results in part from crosstalk between hypoxia-inducible factors (HIFs) and the proto-oncogene c-Myc. Acting alone, HIF and c-Myc partially regulate complex adaptations undertaken by tumor cells growing in low O2. However, acting in concert these transcription factors reprogram metabolism, protein synthesis, and cell cycle progression, to “fine tune” adaptive responses to hypoxic environments

A comprehensive resource for induced pluripotent stem cells from patients with primary tauopathies

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies

Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2

Alzheimer\u27s disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no single study has carefully examined the effect of all of the variants of unknown significance reported in APP, PSEN1 and PSEN2 on Aβ isoform levels in vitro. In this study, we analyzed Aβ isoform levels by ELISA in a cell-based system in which each reported pathogenic and risk variant in APP, PSEN1, and PSEN2 was expressed individually. In order to classify variants for which limited family history data is available, we have implemented an algorithm for determining pathogenicity using available information from multiple domains, including genetic, bioinformatic, and in vitro analyses. We identified 90 variants of unknown significance and classified 19 as likely pathogenic mutations. We also propose that five variants are possibly protective. In defining a subset of these variants as pathogenic, individuals from these families may eligible to enroll in observational studies and clinical trials

Triglycerides promote lipid homeostasis during hypoxic stress by balancing fatty acid saturation

Lipid droplets, which store triglycerides and cholesterol esters, are a prominent feature of clear cell renal cell carcinoma (ccRCC). Although their presence in ccRCC is critical for sustained tumorigenesis, their contribution to lipid homeostasis and tumor cell viability is incompletely understood. Here we show that disrupting triglyceride synthesis compromises the growth of both ccRCC tumors and ccRCC cells exposed to tumor-like conditions. Functionally, hypoxia leads to increased fatty acid saturation through inhibition of the oxygen-dependent stearoyl-CoA desaturase (SCD) enzyme. Triglycerides counter a toxic buildup of saturated lipids, primarily by releasing the unsaturated fatty acid oleate (the principal product of SCD activity) from lipid droplets into phospholipid pools. Disrupting this process derails lipid homeostasis, causing overproduction of toxic saturated ceramides and acyl-carnitines as well as activation of the NF-κB transcription factor. Our work demonstrates that triglycerides promote homeostasis by “buffering” specific fatty acids

HIF Transcription Factor Expression and Induction of Hypoxic Response Genes in a Retroperitoneal Angiosarcoma

Angiosarcoma is a rare and highly aggressive tumor of endothelial origin. The molecular mechanisms driving angiosarcoma growth have not been fully elucidated, although autocrine stimulation by vascular endothelial growth factor (VEGF) secretion may play a role in the pathogenesis of this tumor. We identified a patient with a very rare form of angiosarcoma arising from the retroperitoneum. Immunohistochemical analysis demonstrated widespread up-regulation of the hypoxic response pathway as a mechanism of enhanced VEGF expression. Disordered regulation of the hypoxic response pathway can result in the expression of factors such as VEGF and erythropoietin, which may promote autocrine tumor growth in angiosarcoma

Activation of hypoxia-inducible factor-2 in adipocytes results in pathological cardiac hypertrophy.

BACKGROUND: Obesity can cause structural and functional abnormalities of the heart via complex but largely undefined mechanisms. Emerging evidence has shown that obesity results in reduced oxygen concentrations, or hypoxia, in adipose tissue. We hypothesized that the adipocyte hypoxia-signaling pathway plays an essential role in the development of obesity-associated cardiomyopathy. METHODS AND RESULTS: Using a mouse model in which the hypoxia-inducible factor (HIF) pathway is activated by deletion of the von Hippel-Lindau gene specifically in adipocytes, we found that mice with adipocyte-von Hippel-Lindau deletion developed lethal cardiac hypertrophy. HIF activation in adipocytes results in overexpression of key cardiomyopathy-associated genes in adipose tissue, increased serum levels of several proinflammatory cytokines including interleukin-1β and monocyte chemotactic protein-1, and activation of nuclear factor-κB and nuclear factor of activated T cells in the heart. Interestingly, genetic deletion of Hif2a, but not Hif1a, was able to rescue cardiac hypertrophy and abrogate adipose inflammation. CONCLUSION: We have discovered a previously uncharacterized mechanism underlying a critical and direct role of the adipocyte HIF-2 transcription factor in the development of adipose inflammation and pathological cardiac hypertrophy

Clarifying the translational potential of B-I09

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BNip3 regulates mitochondrial function and lipid metabolism in the liver

BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. While the BNip3 protein is constitutively expressed in adult liver from fed mice, we have shown that its expression is superinduced by fasting of mice, consistent with a role in responses to nutrient deprivation. Loss of BNip3 resulted in increased lipid synthesis in the liver that was associated with elevated ATP levels, reduced AMP-regulated kinase (AMPK) activity, and increased expression of lipogenic enzymes. Conversely, there was reduced β-oxidation of fatty acids in BNip3 null liver and also defective glucose output under fasting conditions. These metabolic defects in BNip3 null liver were linked to increased mitochondrial mass and increased hepatocellular respiration in the presence of glucose. However, despite elevated mitochondrial mass, an increased proportion of mitochondria exhibited loss of mitochondrial membrane potential, abnormal structure, and reduced oxygen consumption. Elevated reactive oxygen species, inflammation, and features of steatohepatitis were also observed in the livers of BNip3 null mice. These results identify a role for BNip3 in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver that has consequences for lipid metabolism and disease