Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F22%3A00554282" target="_blank" >RIV/61388963:_____/22:00554282 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1038/s42255-021-00524-2" target="_blank" >https://doi.org/10.1038/s42255-021-00524-2</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s42255-021-00524-2" target="_blank" >10.1038/s42255-021-00524-2</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth

Popis výsledku v původním jazyce

Tumors can reprogram the functions of metabolic enzymes to fuel malignant growth, however, beyond their conventional functions, key metabolic enzymes have not been found to directly govern cell mitosis. Here, we report that glutamine synthetase (GS) promotes cell proliferation by licensing mitotic progression independently of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple lung and liver cancer cell lines, patient-derived organoids and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of the CDC20-mediated anaphase-promoting complex or cyclosome to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung cancer and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Our findings highlight a moonlighting function of GS in governing mitosis and illustrate how an essential metabolic enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.

Název v anglickém jazyce

Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth

Popis výsledku anglicky

Tumors can reprogram the functions of metabolic enzymes to fuel malignant growth, however, beyond their conventional functions, key metabolic enzymes have not been found to directly govern cell mitosis. Here, we report that glutamine synthetase (GS) promotes cell proliferation by licensing mitotic progression independently of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple lung and liver cancer cell lines, patient-derived organoids and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of the CDC20-mediated anaphase-promoting complex or cyclosome to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung cancer and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Our findings highlight a moonlighting function of GS in governing mitosis and illustrate how an essential metabolic enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GJ18-24473Y" target="_blank" >GJ18-24473Y: Strategie na identifikaci zranitelnosti rakovinných buněk</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature Metabolism

ISSN

2522-5812

e-ISSN

2522-5812

Svazek periodika

4

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

15

Strana od-do

239-253

Kód UT WoS článku

000753764600001

EID výsledku v databázi Scopus

2-s2.0-85124491133