Reference

Nucleic Acids Res. 2015 Sep 22. pii: gkv923.

Authors

María Pilar de Lucas, Alberto G Sáez, Encarnación Lozano.

Abstract

Blocking mitotic progression has been proposed as an attractive therapeutic strategy to impair proliferation of tumour cells. However, how cells survive during prolonged mitotic arrest is not well understood. We show here that survival during mitotic arrest is affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest results in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK. Oxidative respiration is replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 results in enhanced cell death in mitosis and improves the anti-tumoral efficiency of microtubule poisons in breast cancer cells. Thus, survival of mitotic-arrested cells is limited by their metabolic requirements, a feature with potential implications in cancer therapies aimed to impair mitosis or metabolism in tumour cells.

Description

Aunque los microRNAs (miRNAs) modulen la expresión del 60% de los genes codificantes, suele ser difícil determinar su papel e identificar sus genes diana. En este trabajo, utilizando el organismo modelo Caenorhabditis elegans, se ha podido determinar que la familia de microRNAs (miRNAs) de mir-58 es capaz de regular negativamente la actividad de las rutas de TGFβ mejor conocidas en este nematodo: TGFβ Sma/Mab (regula el tamaño corporal) y TGFβ Dauer (implicada en la entrada en el estadio de resistencia dauer). Esta inhibición por parte de la familia de mir-58 se produce de forma directa sobre el ligando dbl-1 y los receptores daf-1, daf-4 and sma-6 de estas rutas de TGFβ. Adicionalmente, se ha observado un bucle regulatorio negativo entre TGF-β Sma/Mab y los miembros de la familia miR-58 y miR-80. Este estudio sugiere que la interacción entre la familia de mir-58 y genes de la ruta de TGFβ es clave en las decisiones sobre el crecimiento de los animales y la resistencia al estrés en C. elegans y, posiblemente, en otros organismos.

 

UFIEC

 

REFERENCIA DEL GRUPO INVESTIGADOR

Nuestro grupo estaba constituído por su directora, la contratada Ramón y Cajal, Dra. Encarnación Lozano, el Dr. Alberto G. Sáez, y la doctoranda María Pilar de Lucas, además de varios estudiantes de licenciatura en estancias cortas. Formamos parte de la Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), del Instituto de Salud Carlos III. Nuestro trabajo se ha centrado en identificar moduladores de la señalización por TGFβ, contribuyendo así a explicar la versatilidad fenotípica de dicha ruta bioquímica. Para ello utilizamos fundamentalmente el nematodo Caenorhabditis elegans.

Descárgate este artículo aquí.

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Sticholysin, Sphingomyelin, and Cholesterol: A Closer Look at a Tripartite Interaction

01-08-2019

Actinoporins are a group of soluble toxic proteins that bind to membranes containing sphingomyelin (SM) and oli- gomerize to form pores. Sticholysin II (StnII) is a member of the actinoporin...

Read more

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

01-07-2019

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable...

Read more

Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program

03-06-2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process...

Read more

ParB dynamics and the critical role of the CTD in DNA condensation unveiled by combined force-fluorescence measurements

01-05-2019

/Bacillus subtilis/ ParB forms multimeric networks involving non-specific DNA binding leading to DNA condensation. Previously, we found that an excess of the free C-terminal domain (CTD) of ParB impeded DNA...

Read more

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer

01-04-2019

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New...

Read more

p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton

01-03-2019

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct...

Read more

β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice

01-02-2019

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In...

Read more

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

02-01-2019

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of...

Read more

Dynamic acetylation of cytosolic phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions

01-12-2018

Cytosolic phosphoenolpyruvate carboxykinase (PCK1) is considered a gluconeogenic enzyme; however, its metabolic functions and regulatory mechanisms beyond gluconeogenesis are poorly understood. Here, we describe that dynamic acetylation of PCK1 interconverts...

Read more

The Helicase PIF1 Facilitates Resection overSequences Prone to Forming G4 Structures

02-11-2018

DNA breaks are complex lesions that can be repaired either by non-homologous end joining (NHEJ) or by homologous recombination (HR). The decision between these two routes of DNA repair is...

Read more

Protector Members