Notwithstanding that metabolic perturbations and dysregulated protein synthesis are salient features of cancer, the mechanism underlying coordination of cellular energy balance with mRNA translation (which is the most energy consuming process in the cell) is poorly understood. In this review, we focus on recently emerging insights in the molecular underpinnings of the cross-talk between oncogenic kinases, translational apparatus and cellular energy metabolism. In particular, we focus on the central signaling nodes that regulate these processes (e.g. the mechanistic/mammalian target of rapamycin MTOR) and the potential implications of these findings on improving the anti-neoplastic efficacy of oncogenic kinase inhibitors.
Oro Uchenunu, Michael Pollak, Ivan Topisirovic, and Laura Hulea
James F H Pittaway and Leonardo Guasti
Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence worldwide of 0.7–2.0 cases/million/year. Initial staging is the most important factor in determining prognosis. If diagnosed early, complete surgical resection +/− adjuvant treatment can lead to 5-year survival of up to 80%. However, often it is diagnosed late and in advanced disease, 5-year survival is <15% with a high recurrence rate even after radical surgery. The mainstay of adjuvant treatment is with the drug mitotane. Mitotane has a specific cytotoxic effect on steroidogenic cells of the adrenal cortex, but despite this, progression through treatment is common. Developments in genetic analysis in the form of next-generation sequencing, aided by bioinformatics, have enabled high-throughput molecular characterisation of these tumours. This, in addition to a better appreciation of the processes of physiological, homeostatic self-renewal of the adrenal cortex, has furthered our understanding of the pathogenesis of this malignancy. In this review, we have detailed the pathobiology and genetic alterations in adrenocortical carcinoma by integrating current understanding of homeostasis and self-renewal in the normal adrenal cortex with molecular profiling of tumours from recent genetic analyses. Improved understanding of the mechanisms involved in self-renewal and stem cell hierarchy in normal human adrenal cortices, together with the identification of cell populations likely to be co-opted by oncogenic mutations, will enable further progress in the definition of the molecular pathways involved in the pathogenesis of ACC. The combination of these advances eventually will lead to the development of novel, effective and personalised strategies to eradicate molecularly annotated ACCs.
Hannah E Lapp, Andrew A Bartlett, and Richard G Hunter
Glucocorticoids have long been recognized for their role in regulating the availability of energetic resources, particularly during stress. Furthermore, bidirectional connections between glucocorticoids and the physiology and function of mitochondria have been discovered over the years. However, the precise mechanisms by which glucocorticoids act on mitochondria have only recently been explored. Glucocorticoids appear to regulate mitochondrial transcription via activation of glucocorticoid receptors (GRs) with elevated circulating glucocorticoid levels following stress. While several mechanistic questions remain, GR and other nuclear transcription factors appear to have the capacity to substantially alter mitochondrial transcript abundance. The regulation of mitochondrial transcripts by stress and glucocorticoids will likely prove functionally relevant in many stress-sensitive tissues including the brain.
Louise K Metcalfe, Greg C Smith, and Nigel Turner
Essential elements of all cells – lipids – play important roles in energy production, signalling and as structural components. Despite these critical functions, excessive availability and intracellular accumulation of lipid is now recognised as a major factor contributing to many human diseases, including obesity and diabetes. In the context of these metabolic disorders, ectopic deposition of lipid has been proposed to have deleterious effects on insulin action. While this relationship has been recognised for some time now, there is currently no unifying mechanism to explain how lipids precipitate the development of insulin resistance. This review summarises the evidence linking specific lipid molecules to the induction of insulin resistance, describing some of the current controversies and challenges for future studies in this field.
Claire Glister, Sheena L Regan, Moafaq Samir, and Phil G Knight
Bone morphogenetic proteins (BMPs) are firmly implicated as intra-ovarian regulators of follicle function and steroidogenesis, but information is lacking regarding the regulation of BMP signalling by extracellular binding proteins co-expressed in the ovary. In this study, we compared the abilities of four BMP-binding proteins (gremlin, noggin, chordin, follistatin) to antagonize the action of four different BMPs (BMP2 BMP4, BMP6, BMP7) on LH-induced androstenedione secretion by bovine theca cells in primary culture. Expression of the four BMP-binding proteins and BMPs investigated here has previously been documented in bovine follicles. All four BMPs suppressed androstenedione secretion by >85%. Co-treatment with gremlin antagonized BMP2- and, less potently, BMP4-induced suppression of androgen secretion but did not affect responses to BMP6 and BMP7. Noggin antagonized the effects of three BMPs (rank order: BMP4 > BMP2 > BMP7) but did not affect the response to BMP6. Follistatin partially reversed the suppressive effects of BMP6 on androgen secretion but did not affect BMP2, BMP4 and BMP7 action. Chordin had no effect on the response to any of the four BMPs. BMP6 treatment upregulated thecal expression of GREM1, NOG, CHRD and SMAD6 mRNA whilst inhibiting expression of the four BMPs. Taken together with previous work documenting the intra-ovarian expression of different BMPs, BMP-binding proteins and signalling receptors, these observations reinforce the conclusion that extracellular binding proteins selectively modulate BMP-dependent alterations in thecal steroidogenesis. As such they likely constitute an important regulatory component of this and other intra-ovarian actions of BMPs.
Xueting Wang, Zhiran Zou, Zhihui Yang, Shan Jiang, Yapeng Lu, Dan Wang, Zhangji Dong, Sha Xu, and Li Zhu
Hypoxia-inducible factor-1 (HIF1) is a critical transcription factor involved in cell response to hypoxia. Under physiological conditions, its ‘a’ subunit is rapidly degraded in most tissues except testes. HIF1 is stably expressed in Leydig cells, which are the main source of testosterone for male, and might bind to the promoter region of steroidogenic acute regulatory protein (STAR), which is necessary for the testosterone synthesis, according to software analysis. This study aims to identify the binding sites of HIF1 on Star promoter and its transcriptional regulation of STAR to affect testosterone synthesis. Testosterone level and steroid synthesis-related proteins were determined in male Balb/C mice exposed to hypoxia (8% O2). While HIF1 was upregulated, the testosterone level was significantly decreased. This was further confirmed by in vitro experiments with rat primary Leydig cells or TM3 cells exposed to hypoxia (1% O2), CoCl2 or DFX to raise HIF1. The decline of testosterone was reversed by pregnenolone but not cAMP, indicating the cholesterol transport disorder as the main cause. In agreement, STAR expression level was decreased in response to HIF1, while 3b-hydroxysteroid dehydrogenase, 17b-hydroxysteroid dehydrogenase and p450scc did not exhibit significant changes. By ChIP, EMSA supershift and dual-luciferase reporter assays, HIF1 was found to bind to the Star promoter region and repress the expression of STAR. Mutation assays identified three HIF1-binding sites on mouse Star promoter. These findings indicate that HIF1 represses STAR transcription through directly binding to the Staar promoter at −2082/−2078, −2064/−2060 and −1910/−1906, leading to the negative regulation of testosterone synthesis.
Biswapriya B Misra, Carl Langefeld, Michael Olivier, and Laura A Cox
With the rapid adoption of high-throughput omic approaches to analyze biological samples such as genomics, transcriptomics, proteomics and metabolomics, each analysis can generate tera- to peta-byte sized data files on a daily basis. These data file sizes, together with differences in nomenclature among these data types, make the integration of these multi-dimensional omics data into biologically meaningful context challenging. Variously named as integrated omics, multi-omics, poly-omics, trans-omics, pan-omics or shortened to just ‘omics’, the challenges include differences in data cleaning, normalization, biomolecule identification, data dimensionality reduction, biological contextualization, statistical validation, data storage and handling, sharing and data archiving. The ultimate goal is toward the holistic realization of a ‘systems biology’ understanding of the biological question. Commonly used approaches are currently limited by the 3 i’s – integration, interpretation and insights. Post integration, these very large datasets aim to yield unprecedented views of cellular systems at exquisite resolution for transformative insights into processes, events and diseases through various computational and informatics frameworks. With the continued reduction in costs and processing time for sample analyses, and increasing types of omics datasets generated such as glycomics, lipidomics, microbiomics and phenomics, an increasing number of scientists in this interdisciplinary domain of bioinformatics face these challenges. We discuss recent approaches, existing tools and potential caveats in the integration of omics datasets for development of standardized analytical pipelines that could be adopted by the global omics research community.
Quinn Dufurrena, Nils Bäck, Richard Mains, Louis Hodgson, Herbert Tanowitz, Prashant Mandela, Betty Eipper, and Regina Kuliawat
Key features for progression to pancreatic β-cell failure and disease are loss of glucose responsiveness and an increased ratio of secreted proinsulin to insulin. Proinsulin and insulin are stored in secretory granules (SGs) and the fine-tuning of hormone output requires signal-mediated recruitment of select SG populations according to intracellular location and age. The GTPase Rac1 coordinates multiple signaling pathways that specify SG release, and Rac1 activity is controlled in part by GDP/GTP exchange factors (GEFs). To explore the function of two large multidomain GEFs, Kalirin and Trio in β-cells, we manipulated their Rac1-specific GEF1 domain activity by using small-molecule inhibitors and by genetically ablating Kalirin. We examined age-related SG behavior employing radiolabeling protocols. Loss of Kalirin/Trio function attenuated radioactive proinsulin release by reducing constitutive-like secretion and exocytosis of 2-h-old granules. At later chase times or at steady state, Kalirin/Trio manipulations decreased glucose-stimulated insulin output. Finally, use of a Rac1 FRET biosensor with cultured β-cell lines demonstrated that Kalirin/Trio GEF1 activity was required for normal rearrangement of Rac1 to the plasma membrane in response to glucose. Rac1 activation can be evoked by both glucose metabolism and signaling through the incretin glucagon-like peptide 1 (GLP-1) receptor. GLP-1 addition restored Rac1 localization/activity and insulin secretion in the absence of Kalirin, thereby assigning Kalirin’s participation to stimulatory glucose signaling.
Yisheng Yang, Stephanie Workman, and Megan J Wilson
The body of knowledge surrounding reproductive development spans the fields of genetics, anatomy, physiology and biomedicine, to build a comprehensive understanding of the later stages of reproductive development in humans and animal models. Despite this, there remains much to learn about the bi-potential progenitor structure that the ovary and testis arise from, known as the genital ridge (GR). This tissue forms relatively late in embryonic development and has the potential to form either the ovary or testis, which in turn produce hormones required for the development of the rest of the reproductive tract. It is imperative that we understand the genetic networks underpinning GR development if we are to begin to understand abnormalities in the adult. This is particularly relevant in the contexts of disorders of sex development (DSDs) and infertility, two conditions that many individuals struggle with worldwide, with often no answers as to their aetiology. Here, we review what is known about the genetics of GR development. Investigating the genetic networks required for GR formation will not only contribute to our understanding of the genetic regulation of reproductive development, it may in turn open new avenues of investigation into reproductive abnormalities and later fertility issues in the adult.
Ming Zhu, Meng Wang, Yijun Chen, and Chao Zhang
Melanocortin receptor accessory protein 2 (MRAP2) plays an important role in regulating melanocortin receptors. In zebrafish, MRAP2a and MRAP2b show distinct pharmacological effects on MC4R activity, but how MRAP2 protein regulates other zebrafish melanocortin receptors is barely studied. Zebrafish have two mc5r genes: mc5ra and mc5rb, it is still vague which one is the homologous isoform to the mammalian paralog. Here, we utilize synteny and phylogenetic analysis to demonstrate the evolutionary conservation of zebrafish MC5Ra and MC5Rb among different species. We also show that MRAP2a and MRAP2b could interact and regulate surface expression of two MC5R receptors. Bimolecular fluorescence complementation (BiFC) studies suggest that zebrafish MC5Rs could form homo- and heterodimers, which are suppressed by co-expression with MRAP2 proteins. In comparison with mammalian MC5R-MRAP2 system and different pharmacological effects of zMRAP2 protein on MC5Rs, zmc5ra is identified as the evolutionary homologous paralog to the mammals, and it is regulated by metabolic state in zebrafish brain region.