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How do organisms, organs, tissues and cells change their fate when they age towards senescence and death? Plant leaves provide a unique window to explore this question because they show reproducible life history and are readily ac...
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How do organisms, organs, tissues and cells change their fate when they age towards senescence and death? Plant leaves provide a unique window to explore this question because they show reproducible life history and are readily accessible for experimental assays. Throughout their lifespan, leaves undergo a series of developmental, physiological and metabolic transitions that culminate in senescence and death. Leaf senescence is an 'altruistic death' that allows for the degradation of the nutrients that are produced during the growth phase of the leaf and their redistribution to developing seeds or other parts of the plant, and thus is a strategy that has evolved to maximize the fitness of the plant. During the past decade, there has been significant progress towards understanding the key molecular principles of leaf senescence using genetic and molecular studies, as well as 'omics' analyses. It is now apparent that leaf senescence is a highly complex genetic program that is tightly controlled by multiple layers of regulation, including at the level of chromatin and transcription, as well as by post-transcriptional, translational and post-translational regulation. This Commentary discusses the latest understandings and insights into the underlying molecular mechanisms, and presents the perspectives necessary to enable our systemlevel understanding of leaf senescence, together with their possible implications for aging in general.
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PTEN (Phosphatase and tensin homolog deleted on chromosome ten) is a tumor suppressor that is frequently mutated in most human cancers. PTEN is a lipid and protein phosphatase that antagonizes PI3K/AKT pathway through lipid phosph...
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PTEN (Phosphatase and tensin homolog deleted on chromosome ten) is a tumor suppressor that is frequently mutated in most human cancers. PTEN is a lipid and protein phosphatase that antagonizes PI3K/AKT pathway through lipid phosphatase activity at the plasma membrane. More recent studies showed that, in addition to the putative role of PTEN as a PI(3,4,5)P3 3-phosphatase, it is a PI(3,4)P2 3-phosphatase during stimulation of class I PI3K signaling pathway by growth factor. Although PTEN tumor suppressor function via it's lipid phosphatase activity occurs primarily in the plasma membrane, it can also be found in the nucleus, in cytoplasmic organelles and extracellular space. PTEN has also shown phosphatase independent functions in the nucleus. PTEN can exit from the cell through exosomal export or secretion and has a tumor suppressor function in adjacent cells. PTEN has a critical role in growth, the cell cycle, protein synthesis, survival, DNA repair and migration. Understanding the regulation of PTEN function, activity, stability, localization and its dysregulation outcomes and also the intracellular and extracellular role of PTEN and paracrine role of PTEN-L in tumor cells as an exogenous therapeutic agent can help to improve clinical conceptualization and treatment of cancer.
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The concept of the 'program' is widely used by developmental biologists and generally everyone knows what it means. However, with the advent of Systems Biology there is an influx into the biological sciences of researchers from ot...
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The concept of the 'program' is widely used by developmental biologists and generally everyone knows what it means. However, with the advent of Systems Biology there is an influx into the biological sciences of researchers from other disciplines, suchas computing, mathematics and engineering, in which 'program' is also a technical term. If Systems Biology is to keep its promises, it is important to ensure that everyone engaged in the analysis of programmed processes in living cells is talking the same language. Arising from discussions in two recent conferences (Wingler, 2007; Thomas, 2008), this Letter takes a critical look at the notion of a program as conceived and studied by plant developmental biologists, focusing particularly on our area of interest, leaf senescence.
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Omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFA, C20-24), including eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), are involved in numerous biological processes and have a range of heal...
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Omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFA, C20-24), including eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), are involved in numerous biological processes and have a range of health benefits. Fish have long been considered as the main source of n-3 LC-PUFA in human diets. However, the capacity for endogenous biosynthesis of LC-PUFA from C18 PUFA varies in fish species based on the presence, expression and activity of key enzymes including fatty acyl desaturases (Fads) and elongation of very long-chain fatty acids (Elovl) proteins. In this article, we review progress on the identified Fads and Elovl, as well as the regulatory mechanisms of LC-PUFA biosynthesis both at transcriptional and post-transcriptional levels in teleosts. The most comprehensive advances have been obtained in rabbitfish Siganus canaliculatus, a marine teleost demonstrated to have the entire pathway for LC-PUFA biosynthesis, including the roles of transcription factors hepatocyte nuclear factor 4 alpha (Hnf4 alpha), liver X receptor alpha (Lxr alpha), sterol regulatory element-binding protein 1 (Srebp-1), peroxisome proliferator-activated receptor gamma (Ppar gamma) and stimulatory protein 1 (Sp1), as well as post-transcriptional regulation by individual microRNA (miRNA) or clusters. This research has, for the first time, demonstrated the involvement of Hnf4 alpha, Ppar gamma and miRNA in the regulation of LC-PUFA biosynthesis in vertebrates. The present review provides readers with a relatively comprehensive overview of the progress made into understanding LC-PUFA biosynthetic systems in teleosts, and some insights into improving endogenous LC-PUFA biosynthesis capacity aimed at reducing the dependence of aquafeeds on fish oil while maintaining or increasing flesh LC-PUFA content and the nutritional quality of farmed fish.
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During the development, progression and dissemination of neoplastic lesions, cancer cells hijack normal pathways and mechanisms, especially those involved in repair and embryologic development. These pathways include those involve...
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During the development, progression and dissemination of neoplastic lesions, cancer cells hijack normal pathways and mechanisms, especially those involved in repair and embryologic development. These pathways include those involved in intercellular communication, control of transcription, post-transcriptional regulation of protein production including translation of mRNAs, post-translational protein modifications, e. g., acetylation of proteins, and protein degradation. Small, non-translatable RNAs, especially microRNAs (miRs), are Important components of post-transcriptional control. MiRs are produced from areas of the genome that are not translated into proteins, but may be co-regulated with their associated genes. MiRs bind to the 3' untranslated regions of mRNAs and regulate the expression of genes in most cases by either promoting the degradation of mRNA and/or inhibiting the translation of mRNAs into proteins; thus, miRs usually cause a decrease in protein levels that would be expected if the mRNAs were translated normally. It is early in our understanding of how miRs affect neoplastic processes, but miRs are expressed differentially in most cancers and have been associated with tumor progression, chemoresistance and metastasis. MiRs are present in nanovesicles, such as exosomes, and thus are likely involved in intercellular communication, especially in neoplasia. MiRs are attractive targets for novel therapies of cancer as well as potential biomarkers that might be useful for early detection and diagnosis, and for prediction of therapeutic efficacy. MiRs also could aid and in determining prognosis, evaluating novel therapies, and developing preventive strategies by their use as surrogate end points.
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Gene transcription is regulated with distinct sets of regulatory factors at multiple levels. Transcriptional and post-transcriptional regulation constitute two major regulation modes of gene expression to either activate or repres...
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Gene transcription is regulated with distinct sets of regulatory factors at multiple levels. Transcriptional and post-transcriptional regulation constitute two major regulation modes of gene expression to either activate or repress the initiation of transcription and thereby control the number of proteins synthesized during translation. Disruptions of the proper regulation patterns at transcriptional and post-transcriptional levels are increasingly recognized as causes of human diseases. Consequently, identifying the differential gene expression at transcriptional and post-transcriptional levels respectively is vital to identify potential disease-associated and/or causal genes and understand their roles in the disease development. Here, we proposeda novel method with a linear mixed model that can identify a set of differentially expressed genes at transcriptional and post-transcriptional levels. The simulation and real data analysis showed our method could provide an accurate way to identify genessubject to aberrant transcriptional and post-transcriptional regulation and reveal the potential causal genes that contributed to the diseases.
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BACKGROUND: Pancreatic cancer is characterized by extensive metastasis. Epithelial-mesenchymal transition (EMT) plasticity plays a critical role in tumor progression and metastasis by maintaining the transition between EMT and mes...
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BACKGROUND: Pancreatic cancer is characterized by extensive metastasis. Epithelial-mesenchymal transition (EMT) plasticity plays a critical role in tumor progression and metastasis by maintaining the transition between EMT and mesenchymal-epithelial transition states. Our aim is to understand the molecular events regulating metastasis and EMT plasticity in pancreatic cancer. METHODS: The interactions between a cancer-promoting zinc transporter ZIP4, a zinc-dependent EMT transcriptional factor ZEB1, a coactivator YAP1, and integrin alpha 3 (ITGA3) were examined in human pancreatic cancer cells, clinical specimens, spontaneous mouse models (KPC and KPCZ) and orthotopic xenografts, and 3-dimensional spheroid and organoid models. Correlations between ZIP4, miR-373, and its downstream targets were assessed by RNA in situ hybridization and immunohistochemical staining. The transcriptional regulation of ZEB1, YAP1, and ITGA3 by ZIP4 was determined by chromatin immunoprecipitation, co-immunoprecipitation, and luciferase reporter assays. RESULTS: The Hippo pathway effector YAP1 is a potent transcriptional coactivator and forms a complex with ZEB1 to activate ITGA3 transcription through the YAP1/transcriptional enhanced associate domain (TEAD) binding sites in human pancreatic cancer cells and KPC-derived mouse cells. ZIP4 upregulated YAP1 expression via activation of miR-373 and inhibition of the YAP1 repressor large tumor suppressor 2 kinase (LATS2). Furthermore, upregulation of ZIP4 promoted EMT plasticity, cell adhesion, spheroid formation, and organogenesis both in human pancreatic cancer cells, 3-dimensional spheroid model, xenograft model, and spontaneous mouse models (KPC and KPCZ) through ZEB1/YAP1-ITGA3 signaling axis. CONCLUSION: We demonstrated that ZIP4 activates ZEB1 and YAP1 through distinct mechanisms. The ZIP4-miR-373-LATS2-ZEB1/YAP1-ITGA3 signaling axis has a significant impact on pancreatic cancer metastasis and EMT plasticity.
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? 2023 Elsevier LtdN6-methyladenosine (m6A) RNA methylation is the most abundant form of mRNA modification in eukaryotes and is at the front line of biological and biomedical research. This dynamic and reversible m6A RNA modificat...
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? 2023 Elsevier LtdN6-methyladenosine (m6A) RNA methylation is the most abundant form of mRNA modification in eukaryotes and is at the front line of biological and biomedical research. This dynamic and reversible m6A RNA modification determines the fates of modified RNA molecules at the post-transcriptional level, affecting almost all important biological processes. Notably, m6A is also involved in chromatin and transcriptional regulation, while m6A dysregulation is implicated in various diseases. Here, we review current knowledge of post-transcriptional and transcriptional regulatory mechanisms involving m6A modification. We also discuss their involvement in the occurrence and development of diseases, including cancer, as well as potential theranostic targets, in hope of facilitating the translation of preclinical findings to the clinic.
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A little over a hundred years ago enquiring minds started to follow up on Mendel's discoveries by looking at ways in which genes could produce phenotypic characteristics, such as the nice colors in peas [1]. The formulation of the...
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A little over a hundred years ago enquiring minds started to follow up on Mendel's discoveries by looking at ways in which genes could produce phenotypic characteristics, such as the nice colors in peas [1]. The formulation of the hypothesis of "one gene-one enzyme" is often credited to an English physician A.E. Garrod interested in inborn errors of metabolism [2], and several decades later supported by compelling experimental data obtained by Beadle and Tatum [3]. In 1962 this hypothesis rnorphed into "one gene-one polypeptide" hypothesis, as Vernon Ingram and others realized that proteins other than enzymes seem to obey the same rules [4]. Thus, everything looked orderly.
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ATP-binding cassette subfamily A member 1(ABCA1) protein plays an essential role in a variety of events,such as cholesterol and phospholipid efflux,nascent high-density lipoprotein(HDL) biosynthesis,phospholipid translocation.Thus...
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ATP-binding cassette subfamily A member 1(ABCA1) protein plays an essential role in a variety of events,such as cholesterol and phospholipid efflux,nascent high-density lipoprotein(HDL) biosynthesis,phospholipid translocation.Thus,there has been much research activity aimed at understanding the molecular mechanisms of regulating ABCA1 expression.In this review,we first discuss ABCA1 structure,tissue distribution,cellular localization,and trafficking,as well as its function.Furthermore,current understanding of the molecular mechanisms involved in the regulation of ABCA1 expression is summarized.ABCA1 transcriptional regulation is mediated by a very complicated system,including nuclear receptor systems,factors binding to other sites in the ABCA1 promoter,cytokines,hormones,growth factors,lipid metabolites,enzymes,and other messengers/factors/pathways.In addition,ABCA1 post-transcriptional regulation is mediated by microRNA,long noncoding RNA,RNA-binding proteins,proteases,fatty acids,PDZ proteins,signaling proteins,and other factors.Compared to the transcriptional regulation of ABCA1,which is well established,the post-transcriptional regulation of ABCA1 expression is poorly understood.
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