The catalytic activity of serine hydroxymethyltransferase is essential for denovo nuclear dTMP synthesis in lung cancer cells
| Autor: | Francesca Cutruzzolà, Alessandro Paiardini, Maria Chiara Magnifico, Serena Rinaldo, Angela Tramonti, Giorgio Giardina, Marina Marani, Amani Bouzidi, Alessio Paone, Giulia Guiducci, Valentino Pontecorvi, Roberta Lucchi, Roberto Contestabile, Carlotta Zamparelli |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Protein Conformation PPI Cell quaternary structure Mitochondrion Crystallography X-Ray Serine 03 medical and health sciences cell biology medicine Thymidine Monophosphate Tumor Cells Cultured biochemistry molecular biology Humans Protein Isoforms SGOCM Cell Proliferation Cell Nucleus Glycine Hydroxymethyltransferase Cell growth Chemistry tetramer lung cancer OCM Cell biology Cytosol Crosstalk (biology) 030104 developmental biology medicine.anatomical_structure Serine hydroxymethyltransferase Cancer cell Mutation Mutant Proteins |
| Zdroj: | The FEBS journal 285 (2018): 3238–3253. doi:10.1111/febs.14610 info:cnr-pdr/source/autori:Giardina, Giorgio; Paone, Alessio; Tramonti, Angela; Lucchi, Roberta; Marani, Marina; Magnifico, Maria Chiara; Bouzidi, Amani; Pontecorvi, Valentino; Guiducci, Giulia; Zamparelli, Carlotta; Rinaldo, Serena; Paiardini, Alessandro; Contestabile, Roberto; Cutruzzola, Francesca/titolo:The catalytic activity of serine hydroxymethyltransferase is essential for denovo nuclear dTMP synthesis in lung cancer cells/doi:10.1111%2Ffebs.14610/rivista:The FEBS journal (Print)/anno:2018/pagina_da:3238/pagina_a:3253/intervallo_pagine:3238–3253/volume:285 |
| DOI: | 10.1111/febs.14610 |
| Popis: | Cancer cells reprogramme one-carbon metabolism (OCM) to sustain growth and proliferation. Depending on cell demands, serine hydroxymethyltransferase (SHMT) dynamically changes the fluxes of OCM by reversibly converting serine and tetrahydrofolate (THF) into 5,10-methylene-THF and glycine. SHMT is a tetrameric enzyme that mainly exists in three isoforms; two localize in the cytosol (SHMT1/SHMT2α) and one (SHMT2) in the mitochondria. Both the cytosolic isoforms can also translocate to the nucleus to sustain de novo thymidylate synthesis and support cell proliferation. Finally, the expression levels of the different isoforms are regulated to a certain extent by a yet unknown crosstalk mechanism. We have designed and fully characterized a set of three SHMT1 mutants, which uncouple the oligomeric state of the enzyme from its catalytic activity. We have then investigated the effects of the mutations on SHMT1 nuclear localization, cell viability and crosstalk in lung cancer cells (A549; H1299). Our data reveal that in these cell lines de novo thymidylate synthesis requires SHMT1 to be active, regardless of its oligomeric state. We have also confirmed that the crosstalk between the cytosolic and mitochondrial SHMT actually takes place and regulates the expression of the two isoforms. Apparently, the crosstalk mechanism is independent from the oligomeric state and the catalytic activity of SHMT1. Database Structural data are available in the PDB under the accession number 6FL5. |
| Databáze: | OpenAIRE |
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