Intricate Regulation of Phosphoenolpyruvate Carboxykinase (PEPCK) Isoforms in Normal Physiology and Disease

2019 ◽  
Vol 19 (4) ◽  
pp. 247-272 ◽  
Author(s):  
Venu Seenappa ◽  
Manjunath B. Joshi ◽  
Kapaettu Satyamoorthy
Keyword(s):  
Translational Regulation ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Current Knowledge ◽  
Regulatory Elements ◽  
Copy Number Variations ◽  
Specific Expression ◽  
Physiological Processes ◽  
Clade B ◽  
And Function ◽  
Endogenous Modulators

Background:The phosphoenolpyruvate carboxykinase (PEPCK) isoforms are considered as rate-limiting enzymes for gluconeogenesis and glyceroneogenesis pathways. PEPCK exhibits several interesting features such as a) organelle-specific isoforms (cytosolic and a mitochondrial) in vertebrate clade, b) tissue-specific expression of isoforms and c) organism-specific requirement of ATP or GTP as a cofactor. In higher organisms, PEPCK isoforms are intricately regulated and activated through several physiological and pathological stimuli such as corticoids, hormones, nutrient starvation and hypoxia. Isoform-specific transcriptional/translational regulation and their interplay in maintaining glucose homeostasis remain to be fully understood. Mounting evidence indicates the significant involvement of PEPCK isoforms in physiological processes (development and longevity) and in the progression of a variety of diseases (metabolic disorders, cancer, Smith–Magenis syndrome).Objective:The present systematic review aimed to assimilate existing knowledge of transcriptional and translational regulation of PEPCK isoforms derived from cell, animal and clinical models.Conclusion:Based on current knowledge and extensive bioinformatics analysis, in this review we have provided a comparative (epi)genetic understanding of PCK1 and PCK2 genes encompassing regulatory elements, disease-associated polymorphisms, copy number variations, regulatory miRNAs and CpG densities. We have also discussed various exogenous and endogenous modulators of PEPCK isoforms and their signaling mechanisms. A comprehensive review of existing knowledge of PEPCK regulation and function may enable identification of the underlying gaps to design new pharmacological strategies and interventions for the diseases associated with gluconeogenesis.

scholarly journals Stage-specific Localization and Expression of c-kit in the Adult Human Testis

2009 ◽  
Vol 57 (9) ◽  
pp. 861-869 ◽  
Author(s):  
Sreepoorna K. Unni ◽  
Deepak N. Modi ◽  
Shilpa G. Pathak ◽  
Jayesh V. Dhabalia ◽  
Deepa Bhartiya
Keyword(s):  
Current Knowledge ◽  
Protein Localization ◽  
Immunohistochemical Analysis ◽  
Human Testis ◽  
Specific Expression ◽  
Adult Human ◽  
Kit Receptor ◽  
Specific Localization ◽  
Human Spermatogenesis ◽  
And Function

The c-kit receptor (KIT) and its ligand, stem cell factor (SCF), represent one of the key regulators of testicular formation, development, and function and have been extensively studied in various animal models. The present study was undertaken to characterize the pattern of localization and expression of c-kit in normal adult human testis. Immunohistochemical analysis showed that KIT is expressed in the cytoplasm of spermatogonia, acrosomal granules of spermatids, and Leydig cells. Interestingly, a rather heterogenous pattern of expression of the protein along the basement membrane was observed. Intense protein localization in spermatogonia was detected in stages I–III, whereas low expression was observed in stages IV–VI of the seminiferous epithelium, indicating that the expression of the molecule was stage specific. In situ hybridization studies revealed that the transcripts of the gene were also localized in a similar non-uniform pattern. To the best of our knowledge, such a stage-specific expression of KIT has not been reported previously in the human testis. The results of the present study may expand current knowledge about the c-kit/SCF system in human spermatogenesis.

scholarly journals DNA Methylation Contributes to the Differential Expression Levels of Mecp2 in Male Mice Neurons and Astrocytes

2019 ◽  
Vol 20 (8) ◽  
pp. 1845 ◽  
Author(s):  
Vichithra R.B. Liyanage ◽  
Carl O. Olson ◽  
Robby M. Zachariah ◽  
James R. Davie ◽  
Mojgan Rastegar
Keyword(s):  
Dna Methylation ◽  
Current Knowledge ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Autism Spectrum ◽  
Brain Cells ◽  
Specific Expression ◽  
Expression Levels ◽  
Mecp2 Duplication Syndrome ◽  
Cell Type Specific Expression

Methyl CpG binding protein-2 (MeCP2) isoforms (E1 and E2) are important epigenetic regulators in brain cells. Accordingly, MeCP2 loss- or gain-of-function mutation causes neurodevelopmental disorders, including Rett syndrome (RTT), MECP2 duplication syndrome (MDS), and autism spectrum disorders (ASD). Within different types of brain cells, highest MeCP2 levels are detected in neurons and the lowest in astrocytes. However, our current knowledge of Mecp2/MeCP2 regulatory mechanisms remains largely elusive. It appears that there is a sex-dependent effect in X-linked MeCP2-associated disorders, as RTT primarily affects females, whereas MDS is found almost exclusively in males. This suggests that Mecp2 expression levels in brain cells might be sex-dependent. Here, we investigated the sex- and cell type-specific expression of Mecp2 isoforms in male and female primary neurons and astrocytes isolated from the murine forebrain. Previously, we reported that DNA methylation of six Mecp2 regulatory elements correlated with Mecp2 levels in the brain. We now show that in male brain cells, DNA methylation is significantly correlated with the transcript expression of these two isoforms. We show that both Mecp2 isoforms are highly expressed in male neurons compared to male astrocytes, with Mecp2e1 expressed at higher levels than Mecp2e2. Our data indicate that higher DNA methylation at the Mecp2 regulatory element(s) is associated with lower levels of Mecp2 isoforms in male astrocytes compared to male neurons.

scholarly journals The critical role of Krüppel-like factors in kidney disease

2017 ◽  
Vol 312 (2) ◽  
pp. F259-F265 ◽  
Author(s):  
Sandeep K. Mallipattu ◽  
Chelsea C. Estrada ◽  
John C. He
Keyword(s):  
Current Knowledge ◽  
Critical Role ◽  
Vital Role ◽  
Glomerular Filtration Barrier ◽  
Kidney Fibrosis ◽  
Physiological Processes ◽  
Filtration Barrier ◽  
And Function ◽  
Mammalian Embryonic Development

Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors critical to mammalian embryonic development, regeneration, and human disease. There is emerging evidence that KLFs play a vital role in key physiological processes in the kidney, ranging from maintenance of glomerular filtration barrier to tubulointerstitial inflammation to progression of kidney fibrosis. Seventeen members of the KLF family have been identified, and several have been well characterized in the kidney. Although they may share some overlap in their downstream targets, their structure and function remain distinct. This review highlights our current knowledge of KLFs in the kidney, which includes their pattern of expression and their function in regulating key biological processes. We will also critically examine the currently available literature on KLFs in the kidney and offer some key areas in need of further investigation.

scholarly journals Adeno-Associated Virus Technologies and Methods for Targeted Neuronal Manipulation

2019 ◽  
Author(s):  
Leila Haery ◽  
Benjamin E. Deverman ◽  
Katherine Matho ◽  
Ali Cetin ◽  
Kenton Woodard ◽  
...  
Keyword(s):  
Viral Vectors ◽  
Cell Types ◽  
Regulatory Elements ◽  
Specific Cell ◽  
Specific Expression ◽  
Adeno Associated Virus ◽  
Cell Type Specific Expression ◽  
Cell Type Specific ◽  
And Function ◽  
Novel Applications

AbstractCell-type-specific expression of molecular tools and sensors is critical to construct circuit diagrams and to investigate the activity and function of neurons within the nervous system. Strategies for targeted manipulation include combinations of classical genetic tools such as Cre/loxP and Flp/FRT, use of cis-regulatory elements, targeted knock-in transgenic mice, and gene delivery by AAV and other viral vectors. The combination of these complex technologies with the goal of precise neuronal targeting is a challenge in the lab. This report will discuss the theoretical and practical aspects of combining current technologies and establish best practices for achieving targeted manipulation of specific cell types. Novel applications and tools, as well as areas for development, will be envisioned and discussed.

scholarly journals Bile Acids and Microbiota: Multifaceted and Versatile Regulators of the Liver–Gut Axis

2021 ◽  
Vol 22 (3) ◽  
pp. 1397
Author(s):  
Niklas Grüner ◽  
Jochen Mattner
Keyword(s):  
Bile Acids ◽  
Current Knowledge ◽  
Gut Bacteria ◽  
Intestinal Lumen ◽  
Clostridioides Difficile ◽  
Physiological Processes ◽  
Local Site ◽  
Inflammatory Bowel ◽  
And Function

After their synthesis from cholesterol in hepatic tissues, bile acids (BAs) are secreted into the intestinal lumen. Most BAs are subsequently re-absorbed in the terminal ileum and are transported back for recycling to the liver. Some of them, however, reach the colon and change their physicochemical properties upon modification by gut bacteria, and vice versa, BAs also shape the composition and function of the intestinal microbiota. This mutual interplay of both BAs and gut microbiota regulates many physiological processes, including the lipid, carbohydrate and energy metabolism of the host. Emerging evidence also implies an important role of this enterohepatic BA circuit in shaping mucosal colonization resistance as well as local and distant immune responses, tissue physiology and carcinogenesis. Subsequently, disrupted interactions of gut bacteria and BAs are associated with many disorders as diverse as Clostridioides difficile or Salmonella Typhimurium infection, inflammatory bowel disease, type 1 diabetes, asthma, metabolic syndrome, obesity, Parkinson’s disease, schizophrenia and epilepsy. As we cannot address all of these interesting underlying pathophysiologic mechanisms here, we summarize the current knowledge about the physiologic and pathogenic interplay of local site microbiota and the enterohepatic BA metabolism using a few selected examples of liver and gut diseases.

scholarly journals Overexpression of MdIAA9 confers high tolerance to osmotic stress in transgenic tobacco

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7935 ◽  
Author(s):  
Dong Huang ◽  
Qian Wang ◽  
Dingyue Duan ◽  
Qinglong Dong ◽  
Shuang Zhao ◽  
...  
Keyword(s):  
Abiotic Stresses ◽  
Expression Profiles ◽  
Major Gene ◽  
Gene Families ◽  
Early Response ◽  
Specific Expression ◽  
Woody Perennial ◽  
Physiological Processes ◽  
And Function ◽  
Indole 3 Acetic Acid

Auxin is a plant hormone that takes part in a series of developmental and physiological processes. There are three major gene families that play a role in the early response of auxin and auxin/indole-3-acetic acid (Aux/IAA) is one of these. Although the genomic organization and function of Aux/IAA genes have been recognized in reference plants there have only been a few focused studies conducted with non-model crop plants, especially in the woody perennial species. We conducted a genomic census and expression analysis of Aux/IAA genes in the cultivated apple (Malus × domestica Borkh.). The Aux/IAA gene family of the apple genome was identified and analyzed in this study. Phylogenetic analysis showed that MdIAAs could be categorized into nine subfamilies and that these MdIAA proteins contained four whole or partially conserved domains of the MdIAA family. The spatio-specific expression profiles showed that most of the MdIAAs were preferentially expressed in specific tissues. Some of these genes were significantly induced by treatments with one or more abiotic stresses. The overexpression of MdIAA9 in tobacco (Nicotiana tabacum L.) plants significantly increased their tolerance to osmotic stresses. Our cumulative data supports the interactions between abiotic stresses and plant hormones and provides a theoretical basis for the mechanism of Aux/IAA and drought resistance in apples.

Regulation of kallikrein-related peptidases in the skin – from physiology to diseases to therapeutic options

2013 ◽  
Vol 110 (09) ◽  
pp. 442-449 ◽  
Author(s):  
Jan Fischer ◽  
Ulf Meyer-Hoffert
Keyword(s):  
Serine Protease ◽  
Protease Inhibitors ◽  
Therapeutic Intervention ◽  
Serine Proteases ◽  
Current Knowledge ◽  
Serine Protease Inhibitors ◽  
Specific Expression ◽  
Physiological Processes ◽  
Promising Target ◽  
Protease Activation

SummaryKallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases, which show a tissue-specific expression profile. This made them valuable tumour expression markers. It became evident that KLKs are involved in many physiological processes like semen liquefaction and skin desquamation. More recently, we have learnt that they are involved in many pathophysiological conditions and diseases making them promising target of therapeutic intervention. Therefore, regulation of KLKs raised the interest of numerous reports. Herein, we summarise the current knowledge on KLKs regulation with an emphasis on skin-relevant KLKs regulation processes. Regulation of KLKs takes place on the level of transcription, on protease activation and on protease inactivation. A variety of protease inhibitors has been described to interact with KLKs including the irreversible serine protease inhibitors (SERPINs) and the reversible serine protease inhibitors of Kazal-type (SPINKs). In an attempt to integrate current knowledge, we propose that KLK regulation has credentials as targets for therapeutic intervention.

Clinical and Molecular Characterization of Two Patients with CNTN6 Copy Number Variations

2018 ◽  
Vol 156 (3) ◽  
pp. 144-149 ◽  
Author(s):  
Elisa Tassano ◽  
Sara Uccella ◽  
Thea Giacomini ◽  
Mariasavina Severino ◽  
Patrizia Fiorio ◽  
...  
Keyword(s):  
Gene Dosage ◽  
Single Gene ◽  
Neuronal Cell ◽  
Regulatory Elements ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Chromosome Band ◽  
Protein Coding ◽  
Genes Encoding ◽  
And Function

Submicroscopic chromosomal alterations usually involve different protein-coding genes and regulatory elements that are responsible for rare contiguous gene disorders, which complicate the understanding of genotype-phenotype correlations. Chromosome band 3p26.3 contains 3 genes encoding neuronal cell adhesion molecules: CHL1, CNTN6, and CNTN4. We describe 2 boys aged 8 years and 11 years mainly affected by intellectual disability and autism spectrum disorder, who harbor a paternally inherited 3p26.3 microdeletion and a 3p26.3 microduplication, respectively. Both anomalies involved only the CNTN6 gene, which encodes contactin 6, a member of the contactin family (MIM 607220). Contactins show pronounced brain expression and function. Interestingly, phenotypes in reciprocal microdeletions and microduplications of CNTN6 are very similar. In conclusion, our data, added to those reported in the literature, are particularly significant for understanding the pathogenic effect of single gene dosage alterations. As for other recurrent syndromes with variable phenotype, these findings are challenging in genetic counselling because of an evident variable penetrance.

scholarly journals Runx transcription factors in the development and function of the definitive hematopoietic system

Blood ◽  
2017 ◽  
Vol 129 (15) ◽  
pp. 2061-2069 ◽  
Author(s):  
Marella de Bruijn ◽  
Elaine Dzierzak
Keyword(s):  
Transcription Factors ◽  
Current Knowledge ◽  
Biological Effects ◽  
Regulation Of Gene Expression ◽  
Loss Of Function ◽  
Specific Expression ◽  
Hematopoietic Stem ◽  
Hematopoietic Development ◽  
Cell Lineages ◽  
And Function

AbstractThe Runx family of transcription factors (Runx1, Runx2, and Runx3) are highly conserved and encode proteins involved in a variety of cell lineages, including blood and blood-related cell lineages, during developmental and adult stages of life. They perform activation and repressive functions in the regulation of gene expression. The requirement for Runx1 in the normal hematopoietic development and its dysregulation through chromosomal translocations and loss-of-function mutations as found in acute myeloid leukemias highlight the importance of this transcription factor in the healthy blood system. Whereas another review will focus on the role of Runx factors in leukemias, this review will provide an overview of the normal regulation and function of Runx factors in hematopoiesis and focus particularly on the biological effects of Runx1 in the generation of hematopoietic stem cells. We will present the current knowledge of the structure and regulatory features directing lineage-specific expression of Runx genes, the models of embryonic and adult hematopoietic development that provide information on their function, and some of the mechanisms by which they affect hematopoietic function.

scholarly journals Clade-Specific Differences between Human Immunodeficiency Virus Type 1 Clades B and C: Diversity and Correlations in C3-V4 Regions of gp120

2007 ◽  
Vol 81 (9) ◽  
pp. 4886-4891 ◽  
Author(s):  
S. Gnanakaran ◽  
Dorothy Lang ◽  
Marcus Daniels ◽  
Tanmoy Bhattacharya ◽  
Cynthia A. Derdeyn ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Current Knowledge ◽  
Viral Glycoprotein ◽  
Clade B ◽  
Immunodeficiency Virus ◽  
Clade C ◽  
And Function

ABSTRACT Current knowledge of human immunodeficiency virus type 1 envelope (Env) glycoprotein structure and function is based on studies of clade B viruses. We present evidence of sequence and structural differences in viral glycoprotein gp120 between clades B and C. In clade C, the C3 region α2-helix exhibits high sequence entropy at the polar face but maintains its amphipathicity, whereas in clade B it accommodates hydrophobic residues. The V4 hypervariable domain in clade C is shorter than that in clade B. Generally, shorter V4 loops are incompatible with a glycine occurring in the α2-helix in clade C, an intriguing association that could be exploited to inform Env immunogen design.

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