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Csibi A.,Harvard University | Lee G.,Harvard University | Yoon S.-O.,Harvard University | Tong H.,Dana-Farber Cancer Institute | And 9 more authors.
Current Biology | Year: 2014

Growth-promoting signaling molecules, including the mammalian target of rapamycin complex 1 (mTORC1), drive the metabolic reprogramming of cancer cells required to support their biosynthetic needs for rapid growth and proliferation [1]. Glutamine is catabolyzed to α-ketoglutarate (αKG), a tricarboxylic acid (TCA) cycle intermediate, through two deamination reactions, the first requiring glutaminase (GLS) to generate glutamate and the second occurring via glutamate dehydrogenase (GDH) or transaminases [2]. Activation of the mTORC1 pathway has been shown previously to promote the anaplerotic entry of glutamine to the TCA cycle via GDH. Moreover, mTORC1 activation also stimulates the uptake of glutamine, but the mechanism is unknown [3]. It is generally thought that rates of glutamine utilization are limited by mitochondrial uptake via GLS, suggesting that, in addition to GDH, mTORC1 could regulate GLS. Here we demonstrate that mTORC1 positively regulates GLS and glutamine flux through this enzyme. We show that mTORC1 controls GLS levels through the S6K1-dependent regulation of c-Myc (Myc). Molecularly, S6K1 enhances Myc translation efficiency by modulating the phosphorylation of eukaryotic initiation factor eIF4B, which is critical to unwind its structured 5′ untranslated region (5′UTR). Finally, our data show that the pharmacological inhibition of GLS is a promising target in pancreatic cancers expressing low levels of PTEN. © 2014 Elsevier Ltd All rights reserved.


Varadi M.,Flemish Institute of Biotechnology VIB | Varadi M.,Vrije Universiteit Brussel | Zsolyomi F.,Flemish Institute of Biotechnology VIB | Zsolyomi F.,Vrije Universiteit Brussel | And 6 more authors.
PLoS ONE | Year: 2015

Proteins form large macromolecular assemblies with RNA that govern essential molecular processes. RNA-binding proteins have often been associated with conformational flexibility, yet the extent and functional implications of their intrinsic disorder have never been fully assessed. Here, through large-scale analysis of comprehensive protein sequence and structure datasets we demonstrate the prevalence of intrinsic structural disorder in RNA-binding proteins and domains. We addressed their functionality through a quantitative description of the evolutionary conservation of disordered segments involved in binding, and investigated the structural implications of flexibility in terms of conformational stability and interface formation. We conclude that the functional role of intrinsically disordered protein segments in RNA-binding is two-fold: first, these regions establish extended, conserved electrostatic interfaces with RNAs via induced fit. Second, conformational flexibility enables them to target different RNA partners, providing multi-functionality, while also ensuring specificity. These findings emphasize the functional importance of intrinsically disordered regions in RNA-binding proteins. © 2015 Varadi et al.


PubMed | Loughborough University and Flemish Institute of Biotechnology VIB
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2016

The first signaling peptide discovered and purified was insulin in 1921. However, it was not until 1991 that the first peptide signal, systemin, was discovered in plants. Since the discovery of systemin, peptides have emerged as a potent and diverse class of signaling molecules in plant systems. Peptides consist of small amino acid sequences, which often act as ligands of receptor kinases. However, not all peptides are created equal, and signaling peptides are grouped into several subgroups dependent on the type of post-translational processing they undergo. Here, we focus on the application of synthetic, post-translationally modified peptides (PTMPs) to plant systems, describing several methods appropriate for the use of peptides in Arabidopsis thaliana and crop models.

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