Abstract | INTRODUCTION: RESULTS: The results of our shRNA screen point to glutamate-cysteine ligase catalytic subunit (GCLC), a key enzyme in glutathione synthesis, as a contributor to TSC-related phenotype. GCLC inhibition increased cellular stress and reduced mTOR hyperactivity in TSC2-depleted neurons and SEGA-derived cells. Moreover, patients' brain tubers showed elevated GCLC and stress markers expression. Finally, GCLC inhibition led to growth arrest and death of SEGA-derived cells. CONCLUSIONS: We describe GCLC as a part of redox adaptation in TSC, needed for overgrowth and survival of mutant cells, and provide a potential novel target for SEGA treatment.
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Authors | Anna R Malik, Ewa Liszewska, Agnieszka Skalecka, Malgorzata Urbanska, Anand M Iyer, Lukasz J Swiech, Malgorzata Perycz, Kamil Parobczak, Patrycja Pietruszka, Malgorzata M Zarebska, Matylda Macias, Katarzyna Kotulska, Julita Borkowska, Wieslawa Grajkowska, Magdalena E Tyburczy, Sergiusz Jozwiak, David J Kwiatkowski, Eleonora Aronica, Jacek Jaworski |
Journal | Acta neuropathologica communications
(Acta Neuropathol Commun)
Vol. 3
Pg. 48
(Jul 30 2015)
ISSN: 2051-5960 [Electronic] England |
PMID | 26220190
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Enzyme Inhibitors
- Immunosuppressive Agents
- RNA, Small Interfering
- TSC1 protein, human
- TSC2 protein, human
- Tuberous Sclerosis Complex 1 Protein
- Tuberous Sclerosis Complex 2 Protein
- Tumor Suppressor Proteins
- Green Fluorescent Proteins
- Buthionine Sulfoximine
- TOR Serine-Threonine Kinases
- GCLM protein, human
- Glutamate-Cysteine Ligase
- Sirolimus
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Topics |
- Adolescent
- Animals
- Brain
(pathology)
- Buthionine Sulfoximine
(pharmacology)
- COS Cells
- Cell Proliferation
(drug effects, genetics)
- Child
- Chlorocebus aethiops
- Enzyme Inhibitors
(pharmacology)
- Female
- Glutamate-Cysteine Ligase
(metabolism)
- Green Fluorescent Proteins
(genetics, metabolism)
- Humans
- Immunosuppressive Agents
(pharmacology)
- Male
- Neurons
(metabolism)
- RNA, Small Interfering
(genetics, metabolism, pharmacology)
- Sirolimus
(pharmacology)
- TOR Serine-Threonine Kinases
(metabolism)
- Tuberous Sclerosis
(pathology)
- Tuberous Sclerosis Complex 1 Protein
- Tuberous Sclerosis Complex 2 Protein
- Tumor Suppressor Proteins
(genetics, metabolism)
- Young Adult
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