l-2-Hydroxyglutarate remodeling of the epigenome and epitranscriptome creates a metabolic vulnerability in kidney cancer models.

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule l-2-hydroxyglutarate (l-2HG) is elevated in the most common histology of renal cancer.

Teleological role of L-2-hydroxyglutarate dehydrogenase in the kidney.

L-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule might have physiological roles that extend beyond its association with cancer, as L-2HG levels are elevated in response to hypoxia and during larval development. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH), and loss of L2HGDH leads to elevated L-2HG levels.

PRDM16 suppresses HIF-targeted gene expression in kidney cancer.

Analysis of transcriptomic data demonstrates extensive epigenetic gene silencing of the transcription factor PRDM16 in renal cancer. We show that restoration of PRDM16 in RCC cells suppresses in vivo tumor growth. RNaseq analysis reveals that PRDM16 imparts a predominantly repressive effect on the RCC transcriptome including suppression of the gene encoding semaphorin 5B (SEMA5B).

PGC1α suppresses kidney cancer progression by inhibiting collagen-induced SNAIL expression.

The transcriptional events that promote invasive and metastatic phenotypes in renal cell carcinoma (RCC) remain poorly understood. Here we report that the decreased expression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α) and the increased expression of several genes encoding collagen family members are associated with RCC tumor progression. PGC1α restoration attenuates invasive phenotypes and suppresses tumor progression in vivo.

14-3-3 proteins protect AMPK-phosphorylated ten-eleven translocation-2 (TET2) from PP2A-mediated dephosphorylation.

Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes and has been implicated in cancer and aging because of its role as a global epigenetic modifier. TET2 has a large N-terminal domain and a catalytic C-terminal region. Previous reports have demonstrated that the TET2 catalytic domain remains active independently of the N-terminal domain.

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer.

Purpose: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated.

Experimental Design: Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on and phenotypes.

The role of public communication in decision making for waste management infrastructure.

Modern waste management provision seeks to meet challenging objectives and strategies while reflecting community aspirations and ensuring cost-effective compliance with statutory obligations. Its social acceptability, which affects both what systems (infrastructure) can be put in place and to what extent their implementation will be successful, is a multi-dimensional phenomenon, often not well understood. In light of the growing evidence that decisions to build new infrastructure are often contested by the public, there is a clear need to understand the role of scientific evidence in public perception, particularly as environmental infrastructure delivery is often objected to by the public on environmental grounds.

Point mutations of the mTOR-RHEB pathway in renal cell carcinoma.

Aberrations in the mTOR (mechanistic target of rapamycin) axis are frequently reported in cancer. Using publicly available tumor genome sequencing data, we identified several point mutations in MTOR and its upstream regulator RHEB (Ras homolog enriched in brain) in patients with clear cell renal cell carcinoma (ccRCC), the most common histology of kidney cancer. Interestingly, we found a prominent cluster of hyperactivating mutations in the FAT (FRAP-ATM-TTRAP) domain of mTOR in renal cell carcinoma that led to an increase in both mTORC1 and mTORC2 activities and led to an increased proliferation of cells.

L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer.

Unlabelled: Through unbiased metabolomics, we identified elevations of the metabolite 2-hydroxyglutarate (2HG) in renal cell carcinoma (RCC). 2HG can inhibit 2-oxoglutaratre (2-OG)-dependent dioxygenases that mediate epigenetic events, including DNA and histone demethylation. 2HG accumulation, specifically the d enantiomer, can result from gain-of-function mutations of isocitrate dehydrogenase (IDH1, IDH2) found in several different tumors.

Retinoic acid hypersensitivity promotes peripheral tolerance in recent thymic emigrants.

Whereas thymic education eliminates most self-reactive T cells, additional mechanisms to promote tolerance in the periphery are critical to prevent excessive immune responses against benign environmental Ags and some self-Ags. In this study we show that murine CD4(+) recent thymic emigrants (RTEs) are programmed to facilitate tolerance in the periphery. Both in vitro and in vivo, naive RTEs more readily upregulate Foxp3 than do mature naive cells after stimulation under tolerogenic conditions.

Developmental regulation of Th17-cell capacity in human neonates.

Human neonates are at significantly greater risk of serious infection than immunocompetent adults. In particular, very low birth weight infants in the neonatal intensive care nursery are at high risk of developing life-threatening bacterial and fungal infections. Recent studies have identified Th17 cells as critical mediators of immunity to bacterial and fungal infections at epithelial barriers.

tRNA isoacceptor preference prior to retrovirus Gag-Pol junction links primer selection and viral translation.

An essential step in the replication of all retroviruses is the capture of a cellular tRNA that is used as the primer for reverse transcription. The 3'-terminal 18 nucleotides of the tRNA are complementary to the primer binding site (PBS). Moloney murine leukemia virus (MuLV) preferentially captures tRNA(Pro).

Preferences for the selection of unique tRNA primers revealed from analysis of HIV-1 replication in peripheral blood mononuclear cells.

Background: All human immunodeficiency virus (HIV-1) uses a host tRNALys,3 as the primer for reverse transcription. The tRNALys,3 is bound to a region on the HIV-1 genome, the primer-binding site (PBS), that is complementary to the 18 terminal nucleotides of tRNALys,3. How HIV-1 selects the tRNA from the intracellular milieu is unresolved.

Inhibition of human immunodeficiency virus type 1 replication by siRNA targeted to the highly conserved primer binding site.

The initiation of HIV-1 reverse transcription occurs at an 18-nucleotide sequence in the viral genome designated as the primer binding site (PBS), which is complementary to the 3' terminal nucleotides of tRNA(Lys,3). Since the PBS is highly conserved among all infectious HIV-1, it represents an attractive target for the development of new therapeutics to inhibit viral replication. In this study, we have evaluated three approaches using small interfering RNA (siRNAs) targeted to the PBS for the capacity to inhibit HIV-1 replication.

HIV type 1 that select tRNA(His) or tRNA(Lys1,2) as primers for reverse transcription exhibit different infectivities in peripheral blood mononuclear cells.

The replication in human peripheral blood mononuclear cells (PBMC) of unique HIV-1 that select tRNA(His) or tRNA(Lys1,2) for reverse transcription was compared to the wild-type virus that uses tRNA(Lys,3). HIV-1 with only the primer-binding site (PBS) changed to be complementary to these alternative tRNAs initially replicated more slowly than the wild-type virus in PBMC, although all viruses eventually reached equivalent growth as measured by p24 antigen. Viruses with only a PBS complementary to the 3' terminal 18 nucleotides of tRNA(His) or tRNA(Lys1,2) reverted to use tRNA(Lys3).