scholarly journals Controlled Signaling—Insulin-Like Growth Factor Receptor Endocytosis and Presence at Intracellular Compartments

2021 ◽  
Vol 11 ◽  
Author(s):  
Leonie Rieger ◽  
Rosemary O’Connor
Keyword(s):  
Golgi Apparatus ◽  
Cancer Cells ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Specific Cell ◽  
Receptor Endocytosis ◽  
Intracellular Compartments ◽  
Associated Proteins ◽  
Membrane Compartments ◽  
And Function

Ligand-induced activation of the IGF-1 receptor triggers plasma-membrane-derived signal transduction but also triggers receptor endocytosis, which was previously thought to limit signaling. However, it is becoming ever more clear that IGF-1R endocytosis and trafficking to specific subcellular locations can define specific signaling responses that are important for key biological processes in normal cells and cancer cells. In different cell types, specific cell adhesion receptors and associated proteins can regulate IGF-1R endocytosis and trafficking. Once internalized, the IGF-1R may be recycled, degraded or translocated to the intracellular membrane compartments of the Golgi apparatus or the nucleus. The IGF-1R is present in the Golgi apparatus of migratory cancer cells where its signaling contributes to aggressive cancer behaviors including cell migration. The IGF-1R is also found in the nucleus of certain cancer cells where it can regulate gene expression. Nuclear IGF-1R is associated with poor clinical outcomes. IGF-1R signaling has also been shown to support mitochondrial biogenesis and function, and IGF-1R inhibition causes mitochondrial dysfunction. How IGF-1R intracellular trafficking and compartmentalized signaling is controlled is still unknown. This is an important area for further study, particularly in cancer.

scholarly journals Epigenetic reprogramming of cell identity: lessons from development for regenerative medicine

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Amitava Basu ◽  
Vijay K. Tiwari
Keyword(s):  
Regenerative Medicine ◽  
Cell Types ◽  
Direct Conversion ◽  
Cellular Reprogramming ◽  
Specific Cell ◽  
Cell Type ◽  
Pathological Conditions ◽  
Gene Regulatory ◽  
Induced Pluripotent ◽  
And Function

AbstractEpigenetic mechanisms are known to define cell-type identity and function. Hence, reprogramming of one cell type into another essentially requires a rewiring of the underlying epigenome. Cellular reprogramming can convert somatic cells to induced pluripotent stem cells (iPSCs) that can be directed to differentiate to specific cell types. Trans-differentiation or direct reprogramming, on the other hand, involves the direct conversion of one cell type into another. In this review, we highlight how gene regulatory mechanisms identified to be critical for developmental processes were successfully used for cellular reprogramming of various cell types. We also discuss how the therapeutic use of the reprogrammed cells is beginning to revolutionize the field of regenerative medicine particularly in the repair and regeneration of damaged tissue and organs arising from pathological conditions or accidents. Lastly, we highlight some key challenges hindering the application of cellular reprogramming for therapeutic purposes.

scholarly journals Developmental enhancers and chromosome topology

Science ◽  
2018 ◽  
Vol 361 (6409) ◽  
pp. 1341-1345 ◽  
Author(s):  
Eileen E. M. Furlong ◽  
Michael Levine
Keyword(s):  
Three Dimensional ◽  
Cell Types ◽  
Living Cells ◽  
Specific Cell ◽  
Transcriptional Dynamics ◽  
Spatiotemporal Expression ◽  
Chromosome Topology ◽  
Classical Models ◽  
And Function ◽  
Target Promoters

Developmental enhancers mediate on/off patterns of gene expression in specific cell types at particular stages during metazoan embryogenesis. They typically integrate multiple signals and regulatory determinants to achieve precise spatiotemporal expression. Such enhancers can map quite far—one megabase or more—from the genes they regulate. How remote enhancers relay regulatory information to their target promoters is one of the central mysteries of genome organization and function. A variety of contrasting mechanisms have been proposed over the years, including enhancer tracking, linking, looping, and mobilization to transcription factories. We argue that extreme versions of these mechanisms cannot account for the transcriptional dynamics and precision seen in living cells, tissues, and embryos. We describe emerging evidence for dynamic three-dimensional hubs that combine different elements of the classical models.

scholarly journals Detection of Cell Types Contributing to Cancer From Circulating, Cell-Free Methylated DNA

2021 ◽  
Vol 12 ◽  
Author(s):  
Megan E. Barefoot ◽  
Netanel Loyfer ◽  
Amber J. Kiliti ◽  
A. Patrick McDeed ◽  
Tommy Kaplan ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Types ◽  
Circulating Tumor Dna ◽  
Cancer Diagnostics ◽  
Tissue Homeostasis ◽  
Specific Cell ◽  
Cell Type ◽  
Liquid Biopsies ◽  
Methylated Dna ◽  
Cell Type Specific

Detection of cellular changes in tissue biopsies has been the basis for cancer diagnostics. However, tissue biopsies are invasive and limited by inaccuracies due to sampling locations, restricted sampling frequency, and poor representation of tissue heterogeneity. Liquid biopsies are emerging as a complementary approach to traditional tissue biopsies to detect dynamic changes in specific cell populations. Cell-free DNA (cfDNA) fragments released into the circulation from dying cells can be traced back to the tissues and cell types they originated from using DNA methylation, an epigenetic regulatory mechanism that is highly cell-type specific. Decoding changes in the cellular origins of cfDNA over time can reveal altered host tissue homeostasis due to local cancer invasion and metastatic spread to distant organs as well as treatment responses. In addition to host-derived cfDNA, changes in cancer cells can be detected from cell-free, circulating tumor DNA (ctDNA) by monitoring DNA mutations carried by cancer cells. Here, we will discuss computational approaches to identify and validate robust biomarkers of changed tissue homeostasis using cell-free, methylated DNA in the circulation. We highlight studies performing genome-wide profiling of cfDNA methylation and those that combine genetic and epigenetic markers to further identify cell-type specific signatures. Finally, we discuss opportunities and current limitations of these approaches for implementation in clinical oncology.

scholarly journals Single cell analysis reveals immune cell–adipocyte crosstalk regulating the transcription of thermogenic adipocytes

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Prashant Rajbhandari ◽  
Douglas Arneson ◽  
Sydney K Hart ◽  
In Sook Ahn ◽  
Graciel Diamante ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Single Cell Analysis ◽  
Metabolic Response ◽  
Cell Types ◽  
Specific Cell ◽  
Beneficial Effects ◽  
Thermogenic Adipocytes ◽  
And Function

Immune cells are vital constituents of the adipose microenvironment that influence both local and systemic lipid metabolism. Mice lacking IL10 have enhanced thermogenesis, but the roles of specific cell types in the metabolic response to IL10 remain to be defined. We demonstrate here that selective loss of IL10 receptor α in adipocytes recapitulates the beneficial effects of global IL10 deletion, and that local crosstalk between IL10-producing immune cells and adipocytes is a determinant of thermogenesis and systemic energy balance. Single Nuclei Adipocyte RNA-sequencing (SNAP-seq) of subcutaneous adipose tissue defined a metabolically-active mature adipocyte subtype characterized by robust expression of genes involved in thermogenesis whose transcriptome was selectively responsive to IL10Rα deletion. Furthermore, single-cell transcriptomic analysis of adipose stromal populations identified lymphocytes as a key source of IL10 production in response to thermogenic stimuli. These findings implicate adaptive immune cell-adipocyte communication in the maintenance of adipose subtype identity and function.

scholarly journals Mos in the Oocyte: How to Use MAPK Independently of Growth Factors and Transcription to Control Meiotic Divisions

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Aude Dupré ◽  
Olivier Haccard ◽  
Catherine Jessus
Keyword(s):  
Growth Factors ◽  
Transcriptional Activation ◽  
Biological Activities ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Specific Cell ◽  
Cell Type ◽  
Specific Cell Type ◽  
Mitogen Activated Protein

In many cell types, the mitogen-activated protein kinase (MAPK) also named extracellular signal-regulated kinase (ERK) is activated in response to a variety of extracellular growth factor-receptor interactions and leads to the transcriptional activation of immediate early genes, hereby influencing a number of tissue-specific biological activities, as cell proliferation, survival and differentiation. In one specific cell type however, the female germ cell, MAPK does not follow this canonical scheme. In oocytes, MAPK is activated independently of growth factors and tyrosine kinase receptors, acts independently of transcriptional regulation, plays a crucial role in controlling meiotic divisions, and is under the control of a peculiar upstream regulator, the kinase Mos. Mos was originally identified as the transforming gene of Moloney murine sarcoma virus and its cellular homologue was the first proto-oncogene to be molecularly cloned. What could be the specific roles of Mos that render it necessary for meiosis? Which unique functions could explain the evolutionary cost to have selected one gene to only serve for few hours in one very specific cell type? This review discusses the original features of MAPK activation by Mos and the roles of this module in oocytes.

scholarly journals The neuronal endoplasmic reticulum: its cytochemistry and contribution to the endomembrane system. I. Cell bodies and dendrites.

1983 ◽  
Vol 31 (9) ◽  
pp. 1077-1088 ◽  
Author(s):  
R D Broadwell ◽  
A M Cataldo
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Apparatus ◽  
Cell Types ◽  
Endomembrane System ◽  
Cell Organelles ◽  
Electron Microscopic ◽  
Enzyme Cytochemistry ◽  
G6pase Activity ◽  
Numerous Cell ◽  
Intracellular Compartments

The endoplasmic reticulum (ER) and its contribution to the endomembrane system (i.e., membranes of cell organelles) in the neuron have been investigated in brains of mice by applying electron microscopic enzyme cytochemistry for demonstration of glucose-6-phosphatase (G6Pase) activity. The phosphohydrolytic activity of G6Pase is a well-known cytochemical marker for the ER in numerous cell types. Of the different substrates employed, glucose-6-phosphate and mannose-6-phosphate were the only two with which G6Pase reaction product was seen in the neuronal ER and organelles related morphologically to the ER. G6Pase activity in cell bodies and dendrites was localized consistently within the lumen of the nuclear envelope, rough and smooth ER, lamellar bodies, hypolemmal and subsurface cisternae, and frequently in the cis saccules of the Golgi apparatus. The G6Pase reactive ER appeared as a network of saccules and tubules pervading the cell body and its dendrites. Possible membrane continuities were identified between the ER and the other reactive structures, including the cis half of the Golgi apparatus. Neither G6Pase activity nor reactive ER was associated with the trans Golgi saccules or GERL. G6Pase activity thus serves as a reliable marker for the perikaryal and dendritic ER and related structures. These observations support the theory that the ER is an integral component of the neuronal endomembrane system associated with the transfer of membrane or membrane molecules among intracellular compartments, the packaging and transport of exportable protein, and energy metabolism. G6Pase activity in the ER of axons and terminals is considered in detail in part two of this study.

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 Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Allison N Lau ◽  
Zhaoqi Li ◽  
Laura V Danai ◽  
Anna M Westermark ◽  
Alicia M Darnell ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Heterogeneous Systems ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Specific Cell ◽  
Isolated Cells ◽  
Pancreatic Cancer Cells ◽  
Turn Over ◽  
Different Cell Types

Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue.

scholarly journals Nuclear Pore Complex Acetylation Regulates mRNA Export and Cell Cycle Commitment in Budding Yeast

2021 ◽  
Author(s):  
Mercè Gomar-Alba ◽  
Vasilisa Pozharskaia ◽  
Celia Schaal ◽  
Arun Kumar ◽  
Basile Jacquel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Export ◽  
Mrna Export ◽  
Cell Types ◽  
Nuclear Pore ◽  
Specific Cell ◽  
Nuclear Pore Complexes ◽  
Daughter Cells ◽  
Associated Proteins ◽  
Pore Complexes

AbstractNuclear pore complexes (NPCs) mediate communication between the nucleus and the cytoplasm and regulate gene expression by interacting with transcription and mRNA export factors. Lysine acetyl-transferases (KATs) promote transcription through acetylation of chromatin-associated proteins. We find that Esa1, the KAT subunit of the yeast NuA4 complex, also acetylates the nuclear pore basket component Nup60 to promote mRNA export. Acetylation of Nup60 recruits mRNA export factors to the nuclear basket, including the scaffolding subunit of the Transcription and Export 2 (TREX-2) complex, Sac3. Esa1-dependent nuclear export of mRNAs promotes entry into S phase, and is inhibited by the Hos3 deacetylase in G1 daughter cells to restrain their premature commitment to a new cell division cycle. This mechanism also inhibits expression of the nutrient-regulated GAL1 gene specifically in daughter cells. These results reveal how acetylation contributes to the functional plasticity of NPCs in specific cell types, and demonstrate how the evolutionarily conserved NuA4 complex regulates gene expression dually at the level of transcription and mRNA export, by modifying the nucleoplasmic entrance to nuclear pores.

scholarly journals Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma

2020 ◽  
Author(s):  
Allison N. Lau ◽  
Zhaoqi Li ◽  
Laura V. Danai ◽  
Anna M. Westermark ◽  
Alicia M. Darnell ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Heterogeneous Systems ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Specific Cell ◽  
Isolated Cells ◽  
Pancreatic Cancer Cells ◽  
Turn Over

AbstractTumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between various cell types within a mixed population can be limited by the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in pancreatic cancer organoid-fibroblast co-cultures and in pancreatic tumors. In these contexts, we find pancreatic cancer cells exhibit increased pyruvate carboxylation relative to fibroblasts, and that this flux depends on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells is necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tumor tissue.

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