The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

mTOR Signaling in Growth, Metabolism, and Disease

Transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP) signaling is involved in a vast majority of cellular processes and is fundamentally important throughout life. TGF-β/BMPs have widely recognized roles in bone formation during mammalian development and exhibit versatile regulatory functions in the body. Signaling transduction by TGF-β/BMPs is specifically through both canonical Smad-dependent pathways (TGF-β/BMP ligands, receptors and Smads) and non-canonical Smad-independent signaling pathway (e.g. p38 mitogen-activated protein kinase pathway, MAPK). Following TGF-β/BMP induction, both the Smad and p38 MAPK pathways converge at the Runx2 gene to control mesenchymal precursor cell differentiation. The coordinated activity of Runx2 and TGF-β/BMP-activated Smads is critical for formation of the skeleton. Recent advances in molecular and genetic studies using gene targeting in mice enable a better understanding of TGF-β/BMP signaling in bone and in the signaling networks underlying osteoblast differentiation and bone formation. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in bone from studies of genetic mouse models and human diseases caused by the disruption of TGF-β/BMP signaling. This review also highlights the different modes of cross-talk between TGF-β/BMP signaling and the signaling pathways of MAPK, Wnt, Hedgehog, Notch, and FGF in osteoblast differentiation and bone formation.

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TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation

The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms.

Disorders of Bone Remodeling

Specific interactions between proteins and DNA are fundamental to many biological processes. In this review, we provide a revised view of protein-DNA interactions that emphasizes the importance of the threedimensional structures of both macromolecules. We divide proteinDNA interactions into two categories: those when the protein recognizes the unique chemical signatures of the DNA bases (base readout) and those when the protein recognizes a sequence-dependent DNA shape (shape readout). We further divide base readout into those interactions that occur in the major groove from those that occur in the minor groove. Analogously, the readout of the DNA shape is subdivided into global shape recognition (for example, when the DNA helix exhibits an overall bend) and local shape recognition (for example, when a base pair step is kinked or a region of the minor groove is narrow). Based on the >1500 structures of protein-DNA complexes now available in the Protein Data Bank, we argue that individual DNA-binding proteins combine multiple readout mechanisms to achieve DNA-binding specificity. Specificity that distinguishes between families frequently involves base readout in the major groove, whereas shape readout is often exploited for higher resolution specificity, to distinguish between members within the same DNA-binding protein family.

/pdf/origins-of-specificity-in-protein-dna-recognition-2wh7lbzegq.pdf

Origins of Specificity in Protein-DNA Recognition

The Animal Transcription Factor DataBase (AnimalTFDB) is a resource aimed to provide the most comprehensive and accurate information for animal transcription factors (TFs) and cofactors. The AnimalTFDB has been maintained and updated for seven years and we will continue to improve it. Recently, we updated the AnimalTFDB to version 3.0 (http://bioinfo.life.hust.edu.cn/AnimalTFDB/) with more data and functions to improve it. AnimalTFDB contains 125,135 TF genes and 80,060 transcription cofactor genes from 97 animal genomes. Besides the expansion in data quantity, some new features and functions have been added. These new features are: (i) more accurate TF family assignment rules; (ii) classification of transcription cofactors; (iii) TF binding sites information; (iv) the GWAS phenotype related information of human TFs; (v) TF expressions in 22 animal species; (vi) a TF binding site prediction tool to identify potential binding TFs for nucleotide sequences; (vii) a separate human TF database web interface (HumanTFDB) was designed for better utilizing the human TFs. The new version of AnimalTFDB provides a comprehensive annotation and classification of TFs and cofactors, and will be a useful resource for studies of TF and transcription regulation.

AnimalTFDB 3.0: a comprehensive resource for annotation and prediction of animal transcription factors.

https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(09)00058-6.pdf

Mechanotransduction in osteoblast regulation and bone disease.

Redox and NF-κB signaling in osteoarthritis.

Transcription factors represent the point of convergence of multiple signaling pathways within eukaryotic cells. Deregulated transcription factors contribute to the pathogenesis of a plethora of human diseases, ranging from diabetes, inflammatory disorders and cardiovascular disease to many cancers, and thus these proteins hold great therapeutic potential. Direct modulation of transcription factor function by small molecules is no longer regarded a Sisyphean task, as recent work in drug discovery has revealed that transcription factors are amenable to drug inhibition. Here in we summarize, recent advances regarding the significance of transcription factors in human diseases and we discuss emerging pharmacological strategies to modulate transcription factor function. J. Cell. Biochem. 117: 2693-2696, 2016. © 2016 Wiley Periodicals, Inc.

Transcription Factor Drug Targets

Posttranslational modifications of histones are considered as critical regulators of gene expression, playing significant role in the pathogenesis and progression of tumors. Trimethylation of histone 3 lysine 9 (H3K9me3), a repressed transcription mark, is mainly regulated by the histone lysine N-methyltransferases (HKMTs), SUV39H1 and SETDB1. The present study investigated the implication of these HKMTs in glioma progression. SUV39H1 and SETDB1 expression was upregulated in glioma cell lines (GOS-3, 1321N1, T98G, U87MG) and in glioma tissues compared to normal brain being positively correlated with grade and histological malignancy. Suppression by siRNA of the two HKMTs for 24 and 48 h resulted in significantly reduced proliferation of GOS-3 and T98G glioma cells with siSUV39H1 effects been most prominent. Furthermore, HKMTs knockdown-induced apoptosis with a high rate of apoptotic cells have been observed after siSUV39H1 and siSETDB1 for both cell lines. Additionally, suppression of the two HKMTs reduced cell migration and clonogenic ability of both glioma cell lines. Our results indicate overexpression of SETDB1 and SUV39H1 in gliomas. Treatments that alter HKMT expression affect the proliferative and apoptotic rates in glioma cells as well as their migratory and colony formation capacity. These data suggest that both HKMTs and especially SUV39H1 may serve as novel biomarkers for future therapeutic targeting of these tumors.

Kostas A. Papavassiliou

Papers

Mechanotransduction in osteoblast regulation and bone disease.

Redox and NF-κB signaling in osteoarthritis.

Transcription Factor Drug Targets

Role of Histone Lysine Methyltransferases SUV39H1 and SETDB1 in Gliomagenesis: Modulation of Cell Proliferation, Migration, and Colony Formation

Hydrogen bonds in protein-DNA complexes: where geometry meets plasticity.