Isp7 Is a Novel Regulator of Amino Acid Uptake in the TOR Signaling Pathway

TOR proteins reside in two distinct complexes, TOR complexes 1 and 2 (TORC1 and TORC2), that are central for the regulation of cellular growth, proliferation, and survival. TOR is also the target for the immunosuppressive and anticancer drug rapamycin. InSchizosaccharomyces pombe, disruption of the TSC complex, mutations in which can lead to the tuberous sclerosis syndrome in humans, results in a rapamycin-sensitive phenotype under poor nitrogen conditions. We show here that the sensitivity to rapamycin is mediated via inhibition of TORC1 and suppressed by overexpression ofisp7+, a member of the family of 2-oxoglutarate-Fe(II)-dependent oxygenase genes. The transcript level ofisp7+is negatively regulated by TORC1 but positively regulated by TORC2. Yet we find extensive similarity between the transcriptome of cells disrupted forisp7+and cells mutated in the catalytic subunit of TORC1. Moreover, Isp7 regulates amino acid permease expression in a fashion similar to that of TORC1 and opposite that of TORC2. Overexpression ofisp7+induces TORC1-dependent phosphorylation of ribosomal protein Rps6 while inhibiting TORC2-dependent phosphorylation and activation of the AGC-like kinase Gad8. Taken together, our findings suggest a central role for Isp7 in amino acid homeostasis and the presence ofisp7+-dependent regulatory loops that affect both TORC1 and TORC2.

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Faculty Opinions recommendation of Light enhanced amino acid uptake by dominant bacterioplankton groups in surface waters of the Atlantic Ocean.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1126015.583128 ◽

2008 ◽

Author(s):

John Hobbie

Keyword(s):

Amino Acid ◽

Atlantic Ocean ◽

Surface Waters ◽

Amino Acid Uptake ◽

Acid Uptake

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Molecular Imaging of Brain Tumor-Associated Epilepsy

Diagnostics ◽

10.3390/diagnostics10121049 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1049

Author(s):

Csaba Juhász ◽

Sandeep Mittal

Keyword(s):

Brain Tumor ◽

Amino Acid ◽

Brain Tumors ◽

Treatment Strategies ◽

Amino Acid Uptake ◽

Seizure Outcome ◽

Acid Uptake ◽

Positron Emission ◽

Oncology Practice ◽

Glioneuronal Tumors

Epilepsy is a common clinical manifestation and a source of significant morbidity in patients with brain tumors. Neuroimaging has a pivotal role in neuro-oncology practice, including tumor detection, differentiation, grading, treatment guidance, and posttreatment monitoring. In this review, we highlight studies demonstrating that imaging can also provide information about brain tumor-associated epileptogenicity and assist delineation of the peritumoral epileptic cortex to optimize postsurgical seizure outcome. Most studies focused on gliomas and glioneuronal tumors where positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques can detect metabolic and biochemical changes associated with altered amino acid transport and metabolism, neuroinflammation, and neurotransmitter abnormalities in and around epileptogenic tumors. PET imaging of amino acid uptake and metabolism as well as activated microglia can detect interictal or peri-ictal cortical increased uptake (as compared to non-epileptic cortex) associated with tumor-associated epilepsy. Metabolic tumor volumes may predict seizure outcome based on objective treatment response during glioma chemotherapy. Advanced MRI, especially glutamate imaging, can detect neurotransmitter changes around epileptogenic brain tumors. Recently, developed PET radiotracers targeting specific glutamate receptor types may also identify therapeutic targets for pharmacologic seizure control. Further studies with advanced multimodal imaging approaches may facilitate development of precision treatment strategies to control brain tumor-associated epilepsy.

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Polyribonucleotide Synthesis and Bacterial Amino Acid Uptake: the Work of Leon A. Heppel

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)47471-0 ◽

2007 ◽

Vol 282 (18) ◽

pp. e13-e15

Author(s):

Nicole Kresge ◽

Robert D. Simoni ◽

Robert L. Hill

Keyword(s):

Amino Acid ◽

Amino Acid Uptake ◽

Acid Uptake

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Amino Acid Transporters on the Guard of Cell Genome and Epigenome

Cancers ◽

10.3390/cancers13010125 ◽

2021 ◽

Vol 13 (1) ◽

pp. 125

Author(s):

Uğur Kahya ◽

Ayşe Sedef Köseer ◽

Anna Dubrovska

Keyword(s):

Amino Acid ◽

Cancer Metabolism ◽

Tumor Imaging ◽

Redox Homeostasis ◽

Amino Acid Uptake ◽

Metabolic Reprogramming ◽

Tumor Evolution ◽

Amino Acid Transporters ◽

Acid Uptake ◽

Growth And Survival

Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools.

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