Control Of Protein Translation Research Articles

Changes in muscle proteomics in the course of the Caudwell Research Expedition to Mt. Everest.

This study employed differential proteomic and immunoassay techniques to elucidate the biochemical mechanisms utilized by human muscle (vastus lateralis) in response to high altitude hypoxia exposure. Two groups of subjects, participating in a medical research expedition (A, n = 5, 19 d at 5300 m altitude; B, n = 6, 66 d up to 8848 m) underwent a ≈ 30% drop of muscular creatine kinase and of glycolytic enzymes abundance. Protein abundance of most enzymes of the tricarboxylic acid cycle and oxidative phosphorylation was reduced both in A and, particularly, in B. Restriction of α-ketoglutarate toward succinyl-CoA resulted in increased prolyl hydroxylase 2 and glutamine synthetase. Both A and B were characterized by a reduction of elongation factor 2 alpha, controlling protein translation, and by an increase of heat shock cognate 71 kDa protein involved in chaperone-mediated autophagy. Increased protein levels of catalase and biliverdin reductase occurred in A alongside a decrement of voltage-dependent anion channels 1 and 2 and of myosin-binding protein C, suggesting damage to the sarcomeric structures. This study suggests that during acclimatization to hypobaric hypoxia the muscle behaves as a producer of substrates activating a metabolic reprogramming able to support anaplerotically the tricarboxylic acid cycle, to control protein translation, to prevent energy expenditure and to activate chaperone-mediated autophagy.

Mammalian target of rapamycin's distinct roles and effectiveness in promoting compensatory axonal sprouting in the injured CNS.

Mammalian target of rapamycin (mTOR) functions as a master sensor of nutrients and energy, and controls protein translation and cell growth. Deletion of phosphatase and tensin homolog (PTEN) in adult CNS neurons promotes regeneration of injured axons in an mTOR-dependent manner. However, others have demonstrated mTOR-independent axon regeneration in different cell types, raising the question of how broadly mTOR regulates axonal regrowth across different systems. Here we define the role of mTOR in promoting collateral sprouting of spared axons, a key axonal remodeling mechanism by which functions are recovered after CNS injury. Using pharmacological inhibition, we demonstrate that mTOR is dispensable for the robust spontaneous sprouting of corticospinal tract axons seen after pyramidotomy in postnatal mice. In contrast, moderate spontaneous axonal sprouting and induced-sprouting seen under different conditions in young adult mice (i.e., PTEN deletion or degradation of chondroitin proteoglycans; CSPGs) are both reduced upon mTOR inhibition. In addition, to further determine the potency of mTOR in promoting sprouting responses, we coinactivate PTEN and CSPGs, and demonstrate that this combination leads to an additive increase in axonal sprouting compared with single treatments. Our findings reveal a developmental switch in mTOR dependency for inducing axonal sprouting, and indicate that PTEN deletion in adult neurons neither recapitulates the regrowth program of postnatal animals, nor is sufficient to completely overcome an inhibitory environment. Accordingly, exploiting mTOR levels by targeting PTEN combined with CSPG degradation represents a promising strategy to promote extensive axonal plasticity in adult mammals.

Translational regulation of the Drosophila post-translational circadian mechanism.

Translational regulation of the Drosophila post-translational circadian mechanism.

PARP12, an Interferon-stimulated Gene Involved in the Control of Protein Translation and Inflammation

Transcriptome analyses have recently identified PARP12, a member of a large family of ADP-ribosyl transferases, as an interferon-induced gene (ISG), whose function remains incompletely characterized. We demonstrate herein that PARP12 is a genuine ISG, whose expressed protein displays at least two distinct subcellular locations and related functions. Upon ectopic expression or exposure to oxidative stress, PARP12 is recruited to stress-granules (SGs), known sites of mRNA translational arrest. Accordingly, PARP12 was found to block mRNA translation, possibly upon association to the translational machinery. Both the N-terminal domain (containing an RNA-binding domain characterized by the presence of five CCCH-type Zn-fingers) and integrity of the catalytic domain are required for this suppressive function. In contrast, stimulation with LPS leads to the localization of PARP12 to p62/SQSTM1 (an adaptor protein involved in innate signaling and autophagy) containing structures, unrelated to SGs. Deletion of the N-terminal domain promotes the association of the protein to p62/SQSTM1, suggesting that the RNA-binding domain is responsible for the subcellular localization of PARP12. Association to p62/SQSTM1 was found to correlate with increased NF-κB signaling, suggesting a role for PARP12 in inflammation. Collectively, these observations suggest that PARP12 can alternate between two distinct subcellular compartments associated to two distinct cellular functions. The present work therefore identifies PARP12 as an ISG with a potential role in cellular defenses against viral infections.

Ginsenoside Rg1 regulates innate immune responses in macrophages through differentially modulating the NF-κB and PI3K/Akt/mTOR pathways.

Ginsenoside Rg1 is one of the major active components of ginseng, which has been shown to regulate the immune response of hosts. However, the mechanism underlying the immunomodulatory effect of Rg1 is incompletely understood. In this study, we aimed to explore whether and how Rg1 regulates the innate immune response in macrophages. The results showed that Rg1 treatment significantly increased tumor necrosis factor (TNF)-α but decreased interleukin-6 (IL-6) protein expression in both lipopolysaccharide (LPS)-activated RAW 264.7 cells and mouse peritoneal macrophages. However, Rg1 reduced the mRNA levels of both cytokines in LPS-activated macrophages, which might be a consequence of decreased activation of IκB and nuclear factor-κB (NF-κB). Importantly, Rg1 treatment further promoted LPS-induced activation of the Akt/mechanistic target of rapamycin (mTOR) pathway, which is critical for controlling protein translation. The elevated Akt/mTOR signaling was likely responsible for increased production of TNF-α protein at the translational level, as suppression of this pathway by LY294002, an inhibitor of the upstream phosphatidylinositol 3-kinase (PI3K), abrogated such an enhancement of TNF-α protein expression even though its mRNA levels were conversely increased. These findings highlight a novel mechanism for Rg1 to regulate the innate immune response in macrophages through differentially modulating the NF-κB and PI3K/Akt/mTOR pathways.

Yeast studies reveal moonlighting functions of the ancient actin cytoskeleton.

Classic functions of the actin cytoskeleton include control of cell size and shape and the internal organization of cells. These functions are manifest in cellular processes of fundamental importance throughout biology such as the generation of cell polarity, cell migration, cell adhesion, and cell division. However, studies in the unicellular model eukaryote Saccharomyces cerevisiae (Baker's yeast) are giving insights into other functions in which the actin cytoskeleton plays a critical role. These include endocytosis, control of protein translation, and determination of protein 3-dimensional shape (especially conversion of normal cellular proteins into prions). Here, we present a concise overview of these new "moonlighting" roles for the actin cytoskeleton and how some of these roles might lie at the heart of important molecular switches. This is an exciting time for researchers interested in the actin cytoskeleton. We show here how studies of actin are leading us into many new and exciting realms at the interface of genetics, biochemistry, and cell biology. While many of the pioneering studies have been conducted using yeast, the conservation of the actin cytoskeleton and its component proteins throughout eukaryotes suggests that these new roles for the actin cytoskeleton may not be restricted to yeast cells but rather may reflect new roles for the actin cytoskeleton of all eukaryotes.

The intra-tumor heterogeneity of cell signaling factors in breast cancer: p4E-BP1 and peIF4E are diffusely expressed and are real potential targets.

Breast cancers and most malignant tumors are composed of heterogeneous tumor cells both at genetic and morphological levels; intra-tumor heterogeneity can be one underlying cause of therapeutic resistance. Classical studies have focused on analyses of the relationship between primary tumors and metastatic dissemination, and on subclone evolution. However, it should be noted that tumor heterogeneity at the level of protein expression (proteomics) has not been yet studied in depth. The differences in protein expression also can play an important role in elucidating the relationship between intra-tumor heterogeneity and resistance to systemic therapy. In fact, in human tumors there is not always a homogeneous expression of many of the crucial factors involved in cell signaling, such as pMAPK, pAKt, pMTOR, even with constitutive oncogenic alterations upstream, such as HER2, PI3 K. Conversely, two of these factors, peIF4E and p4E-BP1, which are downstream, and control protein translation, show a diffuse and strong protein expression. In summary, most of cell signaling factors show a heterogeneous expression, regardless of oncogenic alterations. Tissue heterogeneity could be driven by local factors, including hypoxia. The fact that the phosphorylation of crucial proteins such as 4E-BP1 and eIF4E is observed homogeneously throughout most tumors and are druggable opens the chance to get real potential targets in cancer therapy.

Pharmacological stimulation of the brain serotonin receptor 7 as a novel therapeutic approach for Rett syndrome.

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG-binding protein 2 gene (MECP2) cause >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiological regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R density is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2-308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacological targeting of 5-HT7R improves specific behavioral and molecular manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders associated with intellectual disability.

Oncogenic switching of hypoxia signalling pathways

Tumor hypoxia is strongly associated with an adverse prognosis in cancer, irrespective of treatment modality. Analysis of this association has revealed that hypoxia signalling pathways mediated by hypoxia inducible factor (HIF) are up-regulated in cancer, not only by micro-environment hypoxia, but also by diverse oncogenic signal pathways. Pan-genomic analysis of the HIF transcriptional cascade has demonstrated the massive extent of its actions on gene expression at multiple levels. Direct HIF targets include not only coding RNAs, but regulatory long non-coding RNAs, micro-RNAs and translational control proteins. Physiological pathways that are targeted by the HIF system are not restricted to those with direct actions in oxygen homeostasis, but include biosynthetic metabolic pathways as well as molecules acting on cell differentiation, proliferation, migration and survival decisions. Interestingly, isoform/isoenzyme specific patterns of metabolic gene expression that are induced by HIF map well onto those defined in rapidly proliferating normoxic tumor cells, which are also directly targeted by oncogenic pathways operating in parallel. The implication of oncogenic switching of these massive ‘hard-wired’ parallel physiological pathways for cancer phenotypes will be discussed.

Elevated ATF4 Function in Fibroblasts and Liver of Slow-Aging Mutant Mice

Work in yeast has shown that longevity extension induced by nutrient deprivation, altered ribosomal function, or diminished target of rapamycin action requires the activity of GCN4. We hypothesized that increased activity of ATF4, the mammalian equivalent of yeast GCN4, might be characteristic of mutations that extend mouse life span. Fibroblasts from the skin of two such mutants (Snell dwarf and PAPP-A knockout) were found to have higher levels of ATF4 protein and expression of several ATF4 target genes in responses to amino acid withdrawal, cadmium, hydrogen peroxide, and tunicamycin. ATF4 pathways were also elevated in liver of both kinds of long-lived mutant mice. Thus, a connection between ATF4 pathways and longevity may have deep evolutionary roots, and further studies of ATF4 mechanisms may provide insights into the links between cellular stress resistance, protein translation control, and aging.

Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα

Disruption of protein folding in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a transcriptional and translational control network designed to restore protein homeostasis. Central to the UPR is PKR-like ER kinase (PERK/EIF2AK3) phosphorylation of the α subunit of eIF2 (eIF2α∼P), which represses global translation coincident with preferential translation of mRNAs, such as activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP), that serve to implement UPR transcriptional regulation. In this study, we used sucrose gradient ultracentrifugation and a genome-wide microarray approach to measure changes in mRNA translation during ER stress. Our analysis suggests that translational efficiencies vary over a broad range during ER stress, with the majority of transcripts being either repressed or resistant to eIF2α∼P, whereas a notable cohort of key regulators are subject to preferential translation. From the latter group, we identified the α isoform of inhibitor of Bruton's tyrosine kinase (IBTKα) as being subject to both translational and transcriptional induction during eIF2α∼P in both cell lines and a mouse model of ER stress. Translational regulation of IBTKα mRNA involves stress-induced relief of two inhibitory upstream open reading frames in the 5'-leader of the transcript. Depletion of IBTKα by short hairpin RNA reduced viability of cultured cells coincident with increased caspase 3/7 cleavage, suggesting that IBTKα is a key regulator in determining cell fate during the UPR.

Engineering ribosomal leaky scanning and upstream open reading frames for precise control of protein translation

We have employed upstream open reading frames (uORFs) to systematically tune the translation levels of recombinant proteins. We present the design principles that guided the development of this technology and provide information that may help others in implementing synthetic uORFs for their own applications. We also report on recent applications to our own research projects, including the coupling of uORF and translation initiation site (TIS) engineering with small molecule-inducible post-translational control. Finally, we discuss opportunities to investigate and potentially engineer gene-specific translational responses to cellular stress.

Involvement of PKR in Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by memory troubles followed by aphasia apraxia and agnosia associated with behavioral disturbances. Neuropathological lesions include senile plaques formed by Aβ peptide, neurofibrillary tangles made of hyperphosphorylated tau and neuronal loss. The cause of AD is unknown but Aβ peptide could be responsible for neuronal degeneration. PKR is a stress and pro-apoptotic kinase that controls protein translation via the phosphorylation of the eukariotic initiation factor 2α (eIF2α). Activated PKR accumulates in affected neurons in AD brains and the phosphorylation of PKR can be induced by Aβ peptide. We have found increased levels of PKR in the cerebrospinal fluid of AD patients and PKR level is a good predictor of the cognitive decline. In addition PKR can modulate the levels of BACE1, an APP cleaving enzyme, and can influence tau phosphorylation. Altogether, PKR represents a potential new biomarker and a valid new therapeutic target for neuroprotection in AD.

MiRNA-720 Controls Stem Cell Phenotype, Proliferation and Differentiation of Human Dental Pulp Cells

Dental pulp cells (DPCs) are known to be enriched in stem/progenitor cells but not well characterized yet. Small non-coding microRNAs (miRNAs) have been identified to control protein translation, mRNA stability and transcription, and have been reported to play important roles in stem cell biology, related to cell reprogramming, maintenance of stemness and regulation of cell differentiation. In order to characterize dental pulp stem/progenitor cells and its mechanism of differentiation, we herein sorted stem-cell-enriched side population (SP) cells from human DPCs and periodontal ligament cells (PDLCs), and performed a locked nucleic acid (LNA)-based miRNA array. As a result, miR-720 was highly expressed in the differentiated main population (MP) cells compared to that in SP cells. In silico analysis and a reporter assay showed that miR-720 targets the stem cell marker NANOG, indicating that miR-720 could promote differentiation of dental pulp stem/progenitor cells by repressing NANOG. Indeed, gain-and loss-of-function analyses showed that miR-720 controls NANOG transcript and protein levels. Moreover, transfection of miR-720 significantly decreased the number of cells positive for the early stem cell marker SSEA-4. Concomitantly, mRNA levels of DNA methyltransferases (DNMTs), which are known to play crucial factors during stem cell differentiation, were also increased by miR-720 through unknown mechanism. Finally, miR-720 decreased DPC proliferation as determined by immunocytochemical analysis against ki-67, and promoted odontogenic differentiation as demonstrated by alizarin red staining, as well as alkaline phosphatase and osteopontin mRNA levels. Our findings identify miR-720 as a novel miRNA regulating the differentiation of DPCs.

The far side of auxin signaling: fundamental cellular activities and their contribution to a defined growth response in plants

Recent years have provided us with spectacular insights into the biology of the plant hormone auxin, leaving the impression of a highly versatile molecule involved in virtually every aspect of plant development. A combination of genetics, biochemistry, and cell biology has established auxin signaling pathways, leading to the identification of two distinct modes of auxin perception and downstream regulatory cascades. Major targets of these signaling modules are components of the polar auxin transport machinery, mediating directional distribution of the phytohormone throughout the plant body, and decisively affecting plant development. Alterations in auxin transport, metabolism, or signaling that occur as a result of intrinsic as well as environmental stimuli, control adjustments in morphogenetic programs, giving rise to defined growth responses attributed to the activity of the phytohormone. Some of the results obtained from the analysis of auxin, however, do not fit coherently into a picture of highly specific signaling events, but rather suggest mutual interactions between auxin and fundamental cellular pathways, like the control of intracellular protein sorting or translation. Crosstalk between auxin and these basic determinants of cellular activity and how they might shape auxin effects in the control of morphogenesis are the subject of this review.

Memory accuracy predicts hippocampal mTOR pathway activation following retrieval of contextual fear memory

Prior work suggests that hippocampus-dependent memory undergoes a systems consolidation process such that recent memories are stored in the hippocampus, while older memories are independent of the hippocampus and instead dependent on cortical areas. One problem with interpreting these studies is that memory for the contextual stimuli weakens as time passes between the training event and testing and older memories are often less detailed, making it difficult to determine if memory storage in the hippocampus is related to the age or to the accuracy of the memory. Activity of the mammalian target of rapamycin (mTOR) signaling pathway is known to be important for controlling protein translation necessary for both memory consolidation after initial learning and for the reconsolidation of memory after retrieval. We tested whether p70s6 kinase (p70s6K), a key component of the mTOR signaling pathway, is activated following retrieval of context fear memory in the dorsal hippocampus (DH) and anterior cingulate cortex (ACC) at 1, 10, or 36 days after context fear conditioning. We also tested whether strengthening memory for the contextual stimuli changed p70s6K phosphorylation in these structures 36 days after training. We show that under standard training conditions retrieval of a recently formed memory is initially precise and involves the DH. Over time it loses detail, becomes independent of the DH and depends on the ACC. In a subsequent experiment, we preserved the accuracy of older memories through pre-exposure to the training context. We show that remote memory still involved the DH in animals given pre-exposure. These data support the notion that detailed memories depend on the DH regardless of their age.

Introduction: the unfolded protein response’s role in disease pathophysiology

Introduction: the unfolded protein response’s role in disease pathophysiology

Abstract 1026: Combating resistance to EGFR inhibitors: eIF4B as a novel target.

Abstract Triple negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive cancer that currently has no efficacious therapy. These patients have a high rate of relapse and often develop resistance to chemotherapy. Many TNBCs, both in vitro and in vivo, have elevated levels of epidermal growth factor receptor (EGFR) but are resistant to EGFR inhibitors as a monotherapy. The TNBC cell line, BT20, has increased levels of EGFR and is resistant to EGFR inhibitors. To identify the signaling pathways that remain phosphorylated after treatment with gefitinib, an EGFR tyrosine kinase inhibitor (TKI), we used mass spectrometry based phospho-proteomics. Through these assays we identified many components of the mTOR pathway phosphorylated in the presence of gefitinib and further sought to explore this pathway as a mechanism of resistance to EGFR inhibitors in TNBC. mTOR inhibitors have been investigated in the clinic due to their ability to inhibit the PI3Kinase/Akt pathway thus decreasing cell survival and proliferation. Inhibiting mTOR also importantly inhibits translation. Despite activation of these pathways our TNBC cell lines, BT20, MDA-MB-123, and MDA-MB-468 are resistant to temsirolimus, an mTOR inhibitor. Our studies have found that dual treatment with an mTOR inhibitor and an EGFR TKI has a synergistic effect on decreasing TNBC cell viability, but the mechanism of this synergy is not understood. We have found that the abrogation of both EGFR and mTOR signaling does not alter the phosphorylation status of key signaling pathways including MAPK and Akt. Instead, our preliminary data have identified the translational control protein eIF4B as potentially key fragile point in EGFR and mTOR inhibitor synergy. Therefore, in this study we hypothesized that mTOR inhibition will sensitize TNBC cells to EGFR TKIs through the inhibition of eIF4B phosphorylation. Small molecules have yet to be identified to abrogate the function of eIF4B, which when phosphorylated enhances the helicase activity of eIF4A critical to translation. Therefore, we knockdown eIF4B expression and found a decrease in cell survival comparable to the decrease observed with gefitinib and temsirolimus treatment. In addition, we have identified p70S6K and p90RSK as kinases directly responsible for eIF4B phosphorylation, such that both molecules need to be inactivated in order for eIF4B phosphorylation to be inhibited. This inactivation correlates with a loss of cell growth and viability and a decrease in clonogenic cell survival. Lastly, we have shown that the downstream functions of eIF4B phosphorylation are abrogated with EGFR and mTOR inhibitors. Therefore, taken together these data suggest that in the presence of activated MAPK and AKT, EGFR and mTOR inhibitors have the ability to abrogate cell growth, viability, and survival via disruption of the translational control mechanisms through eIF4B. Citation Format: Julie Madden, Kelly Mueller, Aliccia Bollig-Fischer, Paul Stemmer, Julie Boerner. Combating resistance to EGFR inhibitors: eIF4B as a novel target. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1026. doi:10.1158/1538-7445.AM2013-1026

Glycogen Synthase Kinase-3 Inhibition Enhances Translation of Pluripotency-Associated Transcription Factors to Contribute to Maintenance of Mouse Embryonic Stem Cell Self-Renewal

Maintenance of embryonic stem cell (ESC) self-renewal and pluripotency are controlled by extrinsic factors, molecular signaling pathways and transcriptional regulators. While many of the key players have been studied in depth, how the molecular signals interact with transcription factors of the pluripotency network to regulate their action remains less well understood. Inhibition of glycogen synthase kinase 3 (Gsk-3) has been implicated in the maintenance of mouse ESC pluripotency, although there is contradictory data on its role, with enhancement of cell survival and metabolism, stabilisation of c-Myc and activation of Wnt signalling proposed as potential mechanisms. We have discovered that suppression of Gsk-3 activity leads to enhanced protein levels of key transcriptional regulators of the pluripotency network, notably Nanog, Tbx3 and c-Myc. Protein stability was unchanged following Gsk-3 inhibition, although interestingly, Nanog and Tbx3 proteins were found to have half-lives of 1–3 h, while that of Oct4 protein was longer, at 6 h. We demonstrate that the effects on protein levels seen following inhibition of Gsk-3 are due to both enhanced de novo synthesis of Nanog protein and increases in the proportion of Nanog and Tbx3 RNAs bound to polysomes, findings consistent with Gsk-3 regulating translation of these factors. These effects were not due to changes in regulators of general translation initiation machinery nor mediated via the 5′ or 3′ UTR sequences of Nanog alone. The data we present provide both new conceptual insight into the mechanisms regulated by Gsk-3 that may contribute to ESC self-renewal and, importantly, establish control of protein translation as an additional mechanism involved in modulation of ESC pluripotency.

TOR tour to auxin

Auxin is a principal growth hormone in plants. A study by Schepetilnikov et al (2013) now reports that TOR is activated by auxin and regulates expression of auxin‐responsive genes by facilitating translation reinitiation of mRNAs with uORFs at their 5′ UTRs. In this way, TOR acts at the crossroad of the plasma membrane and nuclear auxin signalling pathways to link auxin with general nutrient signalling. Auxin signalling acts through concentration gradients to regulate developmental processes in plants and the flow of Auxin can be rapidly altered by environmental stimuli resulting in the redirection of plant growth. Auxin concentrations are read and translated into gradients of regulatory proteins, as seen for the PLETHORA (PLT) transcription factors, which determine cellular states, such as stem cell maintenance, cell proliferation, and cell elongation. The currently dominating view is that auxin is perceived by the nuclear TIR/AFB receptors, F‐box proteins, which regulate turnover of the AUX/IAA transcriptional repressors to control gene transcription through a family of AUXIN RESPONSE FACTORs (ARFs; Figure 1; Hayashi, 2012). Schepetilnikov et al (2013) now show that auxin also controls the abundance of key regulators in a post‐transcriptional manner involving selective protein translation. They report that auxin activates TARGET OF RAPAMICIN (TOR), the evolutionary conserved central growth regulator in yeast, plants, and animals. TOR is known to control protein translation through translation initiation in yeast and animals, but its role is less well understood in plants. It was previously …