Current Protein and Peptide Science - Volume 19, Issue 12, 2018

The ability to differentiate into cells of different lineage, such as muscle, bone, cartilage and fat, is the chief value of adult mesenchymal stem cells (MSCs) which can be used with the final aim to regenerate damaged tissue. Due to potential use, as well as importance in tissue development, a number of questions have been raised regarding the molecular mechanisms of MSC differentiation. As one of the crucial mediators in organism development, transforming growth factor beta (TGF-β) superfamily directs MSCs commitment in the selection of differentiation pathways. In this review we aim to give an overview of the current knowledge on the mechanisms of MSCs differentiation, on the involvement of TGF-β superfamily in MSCs differentiation with additional insight into the mutual regulation of microRNAs and TGF-β in MSCs differentiation. Particular focus has been given to the signaling and transcriptional networks governing the differentiation processes.

Transforming growth factor-beta (TGF-β) is well recognized as playing a double role in tumor progression. Its antitumor role takes place in the early stages of cancer development, when TGF-β acts as a repressor of epithelial tumor growth. In advanced stages of cancer development, TGF-β has a tumor stimulating role, acting concomitantly with the increase of cancer cell migration and metastasis. One of the critical features of cancer cells is their ability to migrate and invade the surrounding tissues leading to metastases in different organs. Cancer cells that leave the tumor to infiltrate neighboring tissues and ultimately overtake a distant organ, need a complex and fine-regulated mechanism to move through the barrier imposed by the extracellular matrix (ECM). Therefore, cancer cells express a set of proteinases which are involved in the degradation and turnover of ECM. In particular, the urokinase type plasminogen activator (uPA) and the uPA cell surface receptor play key cellular roles in the enhancement of cell malignance during tumor progression. In normal cells uPA system is finely regulated, while in tumor cells its expression and activity are dysregulated in a way to enhance cells' invasion capacity during tumor progression. TGF-β strongly regulates uPA in cancer from transcriptional expression to enzyme activity. In turn, uPA participates in the activation of secreted latent TGF-β, thus producing a malicious loop which contributes to tumor progression and metastasis. In this review we will analyze the main molecular mechanisms implicated in uPA regulation by TGF-β. Moreover, the specific roles and interaction between TGF-β and uPA system in cancer cells and their impact on tumorigenesis will be portrayed.

This review includes a comprehensive, but succinct, summary on the essentials of TGF- β structure, family members, receptors, and intracellular mediators. Also provided is a select list of original publications that report novel roles and facets of TGF-β in vascular function and signaling in the contexts of health and disease.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide accounting for more than 700 thousand deaths per year. Most of the HCC develops in a cirrhotic liver, a microenvironment where fibrotic tissue replaces parenchymal cells. Thus, there is a close connection between fibrosis and HCC development. Understanding the cellular and molecular mechanisms involved in this process is a crucial step to advance in novel therapeutic or pharmacological strategies to prevent or improve the course of this malignancy. A key molecular player capable of modulating cell growth and fibrosis is the Transforming Growth Factor-beta (TGF-β). Interestingly, TGF-β seems to act like a switch, since it has dual and opposite roles during early and late phases of cancer development. Therefore to develop therapies that target TGF-β signaling pathway for HCC treatment is important to understand the underlying pathogenetic mechanisms at play with special emphasis in the crosstalk between TGF-β and other signaling pathways. In recent years, a plethora of TGR-β have been developed and some of them are under clinical investigations for testing in patients with advanced HCC. In this review, we summarize recent knowledge about the role of TGF-β signaling pathway in HCC progression.

Alzheimer's disease is a neurodegenerative condition affecting millions of people worldwide. Alzheimer's symptoms include memory loss and cognitive decline. Pathologically, the hallmarks of Alzheimer´s are the presence of Amyloid beta-plaques, neurofibrillary tangles, and neuronal loss. Unfortunately, no cure is presently available and current treatments are only symptomatic. Transforming growth factor beta type I (TGF-β1) is a trophic factor involved in neuronal development and synaptic plasticity. Impairment of TGF-β1 signaling is associated with exacerbated Aβ deposition and neurofibrillary tangle formation, which increases neurodegeneration. Aging and chronic inflammation reduce the canonical TGF-β1/Smad signaling, facilitating cytotoxic activation of microglia and microgliamediated neurodegeneration This review gathers together evidence for a neuroprotective role of TGF-β in Alzheimer's disease. Restoring TGF-β1 signaling impairment may be a new pharmacological strategy Alzheimer's treatment.

Among the soluble factors that regulate skeletal muscle function, Transforming Growth Factor type Beta 1 (TGF-β1) is one of the most studied. This factor inhibits myogenesis and regeneration by regulating the activity and function of satellite cells (SCs). Indeed, TGF-β has a central role in muscle pathologies in which there is development of fibrosis and/or atrophy of skeletal muscle. Thus, in this review we present the critical and recent antecedents regarding the mechanisms and cellular targets involved in the effects of TGF-β1 in the muscle, in pathological processes such as the inhibition of regeneration, fibrosis and atrophy. In addition, an update on the development of new strategies with therapeutic potential to inhibit the deleterious actions of TGF-β in skeletal muscle is discussed.

Despite much research on the insect immune system, hormonal regulation of its activity is not well-understood. Previous research on insect neuroendocrinology suggests that neuropeptides may play an important role in the regulation of the insect immune system. Especially recent studies dealing for example with adipokinetic hormones, bursicon or insulin-like peptides provided deeper insights on this issue showing that neuropeptides can modulate various aspects of insect immune responses, both at the molecular and cellular level. The presented review summarizes the current knowledge about the role of neuropeptides regulating the insect immune system activity. Based on structural and functional homology of some vertebrate and insect neuropeptide families, several propositions of insect neuropeptides that might also possess immunotropic activities, but have not been examined for this aspect, are discussed.

The majority of tRNA studies has focused on tRNA molecules as pivotal player in the fundamental process of protein synthesis. Mounting studies have unveiled further functions for tRNA beyond protein synthesis, including non-ribosomal amino acid transfer, and regulation of targeted proteolysis. Post-translational N-terminal arginylation of protein fragments, a non-ribosomal amino acid transfer, is one of the crucial ways by which tRNA participates in various protein degradation trajectories and influences global cellular functions. Previous studies demonstrated a role of arginylation by arginyltransferases (ATEs) in protein degradation, autophagy, and cell death in mammalian cells. Notably, recent investigations in plants have revealed some of the crucial aspects regarding the biochemical nature of Nterminal arginylation and some of its physiological roles. Herein, we review some of the key data on Nterminal arginylation of protein fragments with respect to targeted proteolysis in mammalian cells. Future mechanistic studies using state of the art approaches and physiologically-relevant cellular models are warranted to enhance our molecular understanding of this important yet enigmatic protein modification.

β-galactosidases (EC.3.2.1.23), which hydrolyze lactose to glucose and galactose, have two main applications in the food industry: the production of low-lactose milk and dairy goods for lactose intolerant people, and the generation of galacto-oligosaccharides by transgalactosylation reactions. Due to their thermostability, β-galactosidases from thermophilic microorganisms are very interesting for industrial processes, as high temperatures can increase the initial productivity of the enzyme, provide higher solubility of substrates, and prevent microbial contamination. In the past, it was necessary to cultivate and grow thermophilic microorganisms to discover novel thermozymes, but the development of metagenomic techniques has allowed researchers to access the genomic potential of uncultivated microbes and their enzymes. The present review gives a brief outline of thermophilic β-galactosidases, with a special focus on those obtained through metagenomics. Additionally, the sequences of β-galactosidases found in some public metagenomes from hot springs were studied and compared to other known thermostable β-galactosidases.