scholarly journals Tubulin mRNA stability is sensitive to change in microtubule dynamics caused by multiple physiological and toxic cues

2019 ◽  
Author(s):  
Ivana Gasic ◽  
Sarah A. Boswell ◽  
Timothy J. Mitchison
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Mrna Stability ◽  
Microtubule Dynamics ◽  
Physiological Signal ◽  
Tubulin Genes ◽  
Biological Responses ◽  
Genes Encoding ◽  
Exon Versus ◽  
Tubulin Mrna

AbstractThe localization, mass, and dynamics of microtubules are important in many processes. Cells may actively monitor the state of their microtubules and respond to perturbation, but how this occurs outside mitosis is poorly understood. We used gene expression analysis in quiescent cells to analyze responses to subtle and strong perturbation of microtubules. Genes encoding α-, β, and γ-tubulins, but not δ- or ε-tubulins, exhibited the strongest differential expression response to microtubule-stabilizing versus destabilizing drugs. Q-PCR of exon versus intron sequences confirmed that these changes were caused by regulation of tubulin mRNA stability and not transcription. Using tubulin mRNA stability as a signature to query the GEO database, we find that tubulin genes respond to toxins known to damage microtubules. Importantly, we find many other experimental perturbations, including multiple signaling and metabolic inputs that trigger tubulin differential expression, suggesting their novel role in the regulation of microtubule cytoskeleton. Mechanistic follow up confirms that one important physiological signal, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activity, indeed regulates tubulin mRNA stability via changes in microtubule dynamics. We propose that that tubulin gene expression is regulated as part of many coordinated biological responses, with wide implications in physiology and toxicology. Furthermore, we present a new way to discover microtubule regulation using genomics.

scholarly journals Tubulin mRNA stability is sensitive to change in microtubule dynamics caused by multiple physiological and toxic cues

PLoS Biology ◽  
2019 ◽  
Vol 17 (4) ◽  
pp. e3000225 ◽  
Author(s):  
Ivana Gasic ◽  
Sarah A. Boswell ◽  
Timothy J. Mitchison
Keyword(s):  
Mrna Stability ◽  
Microtubule Dynamics ◽  
Tubulin Mrna

Transcriptional regulation of tubulin gene expression in differentiating trochoblasts during early development of Patella vulgata

Development ◽  
1994 ◽  
Vol 120 (10) ◽  
pp. 2835-2845
Author(s):  
W.G. Damen ◽  
L.A. van Grunsven ◽  
A.E. van Loon
Keyword(s):  
Gene Expression ◽  
Gene Product ◽  
Cell Lines ◽  
Upstream Region ◽  
Tubulin Gene ◽  
Beta Tubulin ◽  
Cell Stage ◽  
Alpha Tubulin ◽  
Tubulin Genes ◽  
Tubulin Mrna

The expression of alpha- and beta-tubulin genes during the early development of the marine mollusk Patella vulgata has been investigated. From the 32-cell stage onwards, an enhanced expression of both alpha- and beta-tubulin mRNAs was detected in the primary trochoblasts. After one additional cleavage, these cells become cleavage-arrested and then form cilia. They are the first cells to differentiate during Patella development. Later, alpha- and beta-tubulin mRNA is also found in the accessory and secondary trochoblasts. Together these three cell-lines form the prototroch, the ciliated locomotory organ of the trochophore larva. The early and abundant expression of tubulin genes precede and accompany cilia formation in the trochoblasts and provides us with an excellent molecular differentiation marker for these cells. Apart from the trochoblasts, tubulin gene expression was also found in other cells at some stages. At the 88-cell stage, elevated tubulin mRNA levels were found around the large nucleus of the mesodermal stem cell 4d. In later stages, tubulin gene expression was detected in the cells that form the flagella of the apical tuft and in the refractive bodies. An alpha-tubulin gene was isolated and characterized. A lacZ fusion gene under control of the 5′ upstream region of this tubulin gene was microinjected into embryos at the two-cell stage. The reporter gene product was only detected in the three trochoblast cell-lines at the same time as tubulin genes were expressed in these cells. Reporter gene product was not detected in any other cells. Thus, this 5′ upstream region of this alpha-tubulin gene contains all the elements required for the correct spatiotemporal pattern of expression.

Structure and arrangement of the beta-tubulin genes of Leishmania tropica

1984 ◽  
Vol 4 (7) ◽  
pp. 1372-1383
Author(s):  
P L Huang ◽  
B E Roberts ◽  
D M Pratt ◽  
J R David ◽  
J S Miller
Keyword(s):  
Protozoan Parasite ◽  
Leishmania Tropica ◽  
Beta Tubulin ◽  
S1 Nuclease ◽  
Alpha Tubulin ◽  
Tubulin Genes ◽  
Repeat Units ◽  
Genes Encoding ◽  
Tubulin Mrna ◽  
Parasite Leishmania

We studied the organization and arrangement of the genes encoding beta-tubulin in the protozoan parasite Leishmania tropica and examined the structure and orientation of the beta-tubulin mRNA relative to the gene. There were found to be eight to nine beta-tubulin genes arranged in an array of direct tandem repeat units with a length of 3.8 kilobase pairs, and they were extremely homologous, if not identical, in sequence. These repeat units did not contain the alpha-tubulin genes. The transcribed sequences within the beta-tubulin genes were localized, and the orientation of the major alpha-tubulin mRNA was mapped on the gene by S1 nuclease analysis.

scholarly journals Structure and arrangement of the beta-tubulin genes of Leishmania tropica.

1984 ◽  
Vol 4 (7) ◽  
pp. 1372-1383 ◽  
Author(s):  
P L Huang ◽  
B E Roberts ◽  
D M Pratt ◽  
J R David ◽  
J S Miller
Keyword(s):  
Protozoan Parasite ◽  
Leishmania Tropica ◽  
Beta Tubulin ◽  
S1 Nuclease ◽  
Alpha Tubulin ◽  
Tubulin Genes ◽  
Repeat Units ◽  
Genes Encoding ◽  
Tubulin Mrna ◽  
Parasite Leishmania

We studied the organization and arrangement of the genes encoding beta-tubulin in the protozoan parasite Leishmania tropica and examined the structure and orientation of the beta-tubulin mRNA relative to the gene. There were found to be eight to nine beta-tubulin genes arranged in an array of direct tandem repeat units with a length of 3.8 kilobase pairs, and they were extremely homologous, if not identical, in sequence. These repeat units did not contain the alpha-tubulin genes. The transcribed sequences within the beta-tubulin genes were localized, and the orientation of the major alpha-tubulin mRNA was mapped on the gene by S1 nuclease analysis.

Brevetoxin 2 alters expression of apoptotic, DNA damage, and cytokine genes in Jurkat cells

2010 ◽  
Vol 30 (3) ◽  
pp. 182-191 ◽  
Author(s):  
Rachel N Murrell ◽  
James E Gibson
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Sodium Channels ◽  
Marine Mammals ◽  
Jurkat Cells ◽  
Voltage Gated ◽  
Dna Damage Signaling ◽  
Voltage Gated Sodium Channels ◽  
Biological Responses ◽  
Genes Encoding

Brevetoxins are potent neurotoxins that exert their toxicity through activation of voltage-gated sodium channels. Exposure to brevetoxins cause severe respiratory inflammation in marine mammals and humans. Brevetoxin activation of voltage-gated sodium channels on immune cells can lead to several biological responses including cell proliferation, gene transcription, cytokine production and even apoptosis. Jurkat E6-1 T cells were treated with brevetoxin 2 for 4 hours at a dose previously shown to induce apoptosis and DNA damage. Changes in gene expression were then assessed via PCR arrays. Gene expression analysis revealed significant change in expression of 17 genes related to apoptosis, 21 genes related to DNA damage signaling, and 19 genes encoding common cytokines. The gene expression data supports the idea that brevetoxins trigger complex reactions involving both inflammation and cell death.

scholarly journals Gene-specific signal transduction between microtubules and tubulin genes in Tetrahymena thermophila.

1995 ◽  
Vol 15 (9) ◽  
pp. 5173-5179 ◽  
Author(s):  
L Gu ◽  
J Gaertig ◽  
L A Stargell ◽  
M A Gorovsky
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Mammalian Cells ◽  
Tetrahymena Thermophila ◽  
Tubulin Gene ◽  
Beta Tubulin ◽  
Alpha Tubulin ◽  
Tubulin Genes ◽  
Cell Biol ◽  
Tubulin Mrna

Mammalian cells regulate tubulin mRNA abundance by a posttranscriptional mechanism dependent on the concentration of tubulin monomer. Treatment of mammalian cells with microtubule-depolymerizing drugs and microtubule-polymerizing drugs causes decreases and increases in tubulin mRNA, respectively (D. W. Cleveland, Curr. Opin. Cell Biol. 1:10-14, 1989). In striking contrast to the case with mammalian cells, perturbation of microtubules in Tetrahymena thermophila by microtubule-depolymerizing or -polymerizing drugs increases the level of the single alpha-tubulin gene message by increasing transcription (L. A. Stargell, D. P. Heruth, J. Gaertig, and M. A. Gorovsky, Mol. Cell. Biol. 12:1443-1450, 1992). In this report we show that antimicrotubule drugs preferentially induce the expression of one of two beta-tubulin genes (BTU1) in T. thermophila. In contrast, deciliation induces expression of both beta-tubulin genes. Tubulin gene expression was examined in a mutant strain created by transformation with an in vitro-mutagenized beta-tubulin gene that conferred resistance to microtubule-depolymerizing drugs and sensitivity to the polymerizing drug taxol and in a strain containing a nitrosoguanidine-induced mutation in the single alpha-tubulin gene that conferred the same pattern of drug sensitivities. In both cases the levels of tubulin mRNA expression from the drug-inducible BTU1 gene in the mutant cells paralleled the altered growth sensitivities to microtubule drugs. These studies demonstrate that T. thermophila has distinct, gene-specific mechanisms for modulating tubulin gene expression depending on whether ciliary or cytoplasmic microtubules are involved. They also show that the cytoplasmic microtubule cytoskeleton itself participates in a signal transduction pathway that regulates specific tubulin gene transcription in T. thermophila.

scholarly journals High-throughput transcriptomic analysis of human primary hepatocyte spheroids exposed to per- and polyfluoroalkyl substances (PFAS) as a platform for relative potency characterization

2021 ◽  
Author(s):  
A Rowan-Carroll ◽  
A Reardon ◽  
K Leingartner ◽  
R Gagné ◽  
A Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cholesterol Biosynthesis ◽  
Health Hazard ◽  
Biological Responses ◽  
Similar Gene Expression Profile ◽  
Transcriptional Changes ◽  
Hazard And Risk ◽  
Hepatocyte Spheroids ◽  
Similar Gene ◽  
Identify Gene Expression

Abstract Per- and poly-fluoroalkyl substances (PFAS) are widely found in the environment because of their extensive use and persistence. Although several PFAS are well studied, most lack toxicity data to inform human health hazard and risk assessment. This study focussed on four model PFAS: perfluorooctanoic acid (PFOA; 8 carbon), perfluorobutane sulfonate (PFBS; 4 carbon), perfluorooctane sulfonate (PFOS; 8 carbon), and perfluorodecane sulfonate (PFDS; 10 carbon). Human primary liver cell spheroids (pooled from 10 donors) were exposed to 10 concentrations of each PFAS and analyzed at four time-points. The approach aimed to: (1) identify gene expression changes mediated by the PFAS; (2) identify similarities in biological responses; (3) compare PFAS potency through benchmark concentration analysis; and (4) derive bioactivity exposure ratios (ratio of the concentration at which biological responses occur, relative to daily human exposure). All PFAS induced transcriptional changes in cholesterol biosynthesis and lipid metabolism pathways, and predicted PPARα activation. PFOS exhibited the most transcriptional activity and had a highly similar gene expression profile to PFDS. PFBS induced the least transcriptional changes and the highest benchmark concentration (i.e., was the least potent). The data indicate that these PFAS may have common molecular targets and toxicities, but that PFOS and PFDS are the most similar. The transcriptomic bioactivity exposure ratios derived here for PFOA and PFOS were comparable to those derived using rodent apical endpoints in risk assessments. These data provide a baseline level of toxicity for comparison with other known PFAS using this testing strategy.

scholarly journals Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karolina Stępniak ◽  
Magdalena A. Machnicka ◽  
Jakub Mieczkowski ◽  
Anna Macioszek ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Genome Mapping ◽  
Malignant Gliomas ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Multiple Tumor ◽  
Genes Encoding ◽  
Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

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