scholarly journals Therapeutic Effect of Rapamycin on Aortic Dissection in Mice

2020 ◽  
Vol 21 (9) ◽  
pp. 3341
Author(s):  
Makiko Hayashi-Hori ◽  
Hiroki Aoki ◽  
Miho Matsukuma ◽  
Ryohei Majima ◽  
Yohei Hashimoto ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Aortic Dissection ◽  
Muscle Development ◽  
Fatal Outcome ◽  
Growth Factor Signaling ◽  
Related Gene ◽  
Observational Period ◽  
Aortic Smooth Muscle ◽  
Mechanistic Target Of Rapamycin ◽  
Cell Cycle Activation

Aortic dissection (AD) is a serious clinical condition that is unpredictable and frequently results in fatal outcome. Although rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has been reported to be effective in preventing aortopathies in mouse models, its mode of action has yet to be clarified. A mouse AD model that was created by the simultaneous administration of β-aminopropionitrile (BAPN) and angiotensin II (AngII) for 14 days. Rapamycin treatment was started either at day 1 or at day 7 of BAPN+AngII challenge, and continued throughout the observational period. Rapamycin was effective both in preventing AD development and in suppressing AD progression. On the other hand, gefitinib, an inhibitor of growth factor signaling, did not show such a beneficial effect, even though both rapamycin and gefitinib suppressed cell cycle activation in AD. Rapamycin suppressed cell cycle-related genes and induced muscle development-related genes in an AD-related gene expression network without a major impact on inflammation-related genes. Rapamycin augmented the activation of Akt1, Akt2, and Stat3, and maintained the contractile phenotype of aortic smooth muscle cells. These findings indicate that rapamycin was effective both in preventing the development and in suppressing the progression of AD, indicating the importance of the mTOR pathway in AD pathogenesis.

scholarly journals Analysis of cell cycle related gene expression in Myb deficient mandible – a pilot study

Bone Reports ◽  
2021 ◽  
Vol 14 ◽  
pp. 100907
Author(s):  
Sabina Stouracova ◽  
Eva Matalova ◽  
Jon Frampton ◽  
Mary Clarke ◽  
Premysl Bartos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Pilot Study ◽  
Related Gene ◽  
Cell Cycle Related Gene

Ethylisopropylamiloride-sensitive pH control mechanisms modulate vascular smooth muscle cell growth

1991 ◽  
Vol 260 (3) ◽  
pp. C581-C588 ◽  
Author(s):  
A. Bobik ◽  
A. Grooms ◽  
P. J. Little ◽  
E. J. Cragoe ◽  
S. Grinpukel
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Mitotic Cell ◽  
Ph Control ◽  
S Phase ◽  
Control Mechanisms ◽  
Aortic Smooth Muscle ◽  
Exchange Activity

The reported effects of alterations in Na-H exchange activity on mitogenesis are variable and appear dependent on the cell type examined. We examined the effects of reductions in ethylisopropylamiloride (EIPA)-sensitive pH-regulating mechanisms including Na-H exchange and alterations in intracellular pH (pHi) on the growth characteristics of rat aortic smooth muscle cells (RASM) cultured in serum-containing bicarbonate-buffered medium. Exposure of RASM replicating in bicarbonate-containing medium to the Na-H exchange inhibitors EIPA, dimethylamiloride (DMA), or amiloride (A) attenuated their replication rate. The order of potency of the inhibitors (EIPA greater than DMA much greater than A) was similar to their documented effects on Na-H exchange activity and to their order of potency for inhibiting recovery from CO2-induced acidosis in these cells. Reductions in pHi induced by lowering extracellular pH also attenuated the incorporation of [3H]-thymidine into DNA, while increases in pHi were associated with an acceleration in the rate of incorporation of [3H]thymidine into DNA. The effects of the Na-H exchange inhibitors on RASM replication were due to a reduction in the ability of the smooth muscle cells to enter the S phase of the mitotic cell cycle. This appeared predominantly the consequence of effects late within the G1 phase of the cell cycle. Concentrations of EIPA that markedly reduced the ability of RASM to enter S phase and to replicate also attenuated the increase in protein synthesis occurring 6-8 h after exposure to serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of Pax-3 expression in the dermomyotome and its role in muscle development

Development ◽  
1994 ◽  
Vol 120 (4) ◽  
pp. 957-971 ◽  
Author(s):  
M. Goulding ◽  
A. Lumsden ◽  
A.J. Paquette
Keyword(s):  
Transcription Factors ◽  
Muscle Development ◽  
Cell Types ◽  
Axial Skeleton ◽  
Mouse Embryos ◽  
Related Gene ◽  
Paired Domain ◽  
Trunk Musculature ◽  
Somitic Mesoderm

The segmented mesoderm in vertebrates gives rise to a variety of cell types in the embryo including the axial skeleton and muscle. A number of transcription factors containing a paired domain (Pax proteins) are expressed in the segmented mesoderm during embryogenesis. These include Pax-3 and a closely related gene, Pax-7, both of which are expressed in the segmental plate and in the dermomyotome. In this paper, we show that signals from the notochord pattern the expression of Pax-3, Pax-7 and Pax-9 in somites and the subsequent differentiation of cell types that arise from the somitic mesoderm. We directly assess the role of the Pax-3 gene in the differentiation of cell types derived from the dermomyotome by analyzing the development of muscle in splotch mouse embryos which lack a functional Pax-3 gene. A population of Pax-3-expressing cells derived from the dermomyotome that normally migrate into the limb are absent in homozygous splotch embryos and, as a result, limb muscles are lost. No abnormalities were detected in the trunk musculature of splotch embryos indicating that Pax-3 is necessary for the development of the limb but not trunk muscle.

Histone H3 transcription in Saccharomyces cerevisiae is controlled by multiple cell cycle activation sites and a constitutive negative regulatory element

1992 ◽  
Vol 12 (12) ◽  
pp. 5455-5463 ◽  
Author(s):  
K B Freeman ◽  
L R Karns ◽  
K A Lutz ◽  
M M Smith
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Cell Division ◽  
Transcriptional Activation ◽  
Regulatory Element ◽  
Histone H3 ◽  
Regulatory Elements ◽  
Cell Division Cycle ◽  
Cell Cycle Activation ◽  
Multiple Cell

The promoters of the Saccharomyces cerevisiae histone H3 and H4 genes were examined for cis-acting DNA sequence elements regulating transcription and cell division cycle control. Deletion and linker disruption mutations identified two classes of regulatory elements: multiple cell cycle activation (CCA) sites and a negative regulatory site (NRS). Duplicate 19-bp CCA sites are present in both the copy I and copy II histone H3-H4 promoters arranged as inverted repeats separated by 45 and 68 bp. The CCA sites are both necessary and sufficient to activate transcription under cell division cycle control. A single CCA site provides cell cycle control but is a weak transcriptional activator, while an inverted repeat comprising two CCA sites provides both strong transcriptional activation and cell division cycle control. The NRS was identified in the copy I histone H3-H4 promoter. Deletion or disruption of the NRS increased the level of the histone H3 promoter activity but did not alter the cell division cycle periodicity of transcription. When the CCA sites were deleted from the histone promoter, the NRS element was unable to confer cell division cycle control on the remaining basal level of transcription. When the NRS element was inserted into the promoter of a foreign reporter gene, transcription was constitutively repressed and did not acquire cell cycle regulation.

scholarly journals Transforming growth factor-beta-induced growth inhibition and cellular hypertrophy in cultured vascular smooth muscle cells.

1988 ◽  
Vol 107 (2) ◽  
pp. 771-780 ◽  
Author(s):  
G K Owens ◽  
A A Geisterfer ◽  
Y W Yang ◽  
A Komoriya
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Muscle Cells ◽  
Tgf Beta ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Cellular Hypertrophy

We have explored the hypothesis that hypertrophy of vascular smooth muscle cells may be regulated, in part, by growth inhibitory factors that alter the pattern of the growth response to serum mitogens by characterizing the effects of the potent growth inhibitor, transforming growth factor-beta (TGF-beta), on both hyperplastic and hypertrophic growth of cultured rat aortic smooth muscle cells. TGF-beta inhibited serum-induced proliferation of rat aortic smooth muscle cells (ED50 = 2 pM); this is consistent with previously reported observations in bovine aortic smooth muscle cells (Assoian et al. 1982. J. Biol. Chem. 258:7155-7160). Growth inhibition was due in part to a greater than twofold increase in the cell cycle transit time in cells that continued to proliferate in the presence of TGF-beta. TGF-beta concurrently induced cellular hypertrophy as assessed by flow cytometric analysis of cellular protein content (47% increase) and forward angle light scatter (32-50% increase), an index of cell size. In addition to being time and concentration dependent, this hypertrophy was reversible. Simultaneous flow cytometric evaluation of forward angle light scatter and cellular DNA content demonstrated that TGF-beta-induced hypertrophy was not dependent on withdrawal of cells from the cell cycle nor was it dependent on growth arrest of cells at a particular point in the cell cycle in that both cycling cells in the G2 phase of the cell cycle and those in G1 were hypertrophied with respect to the corresponding cells in vehicle-treated controls. Chronic treatment with TGF-beta (100 pM, 9 d) was associated with accumulation of cells in the G2 phase of the cell cycle in the virtual absence of cells in S phase, whereas subsequent removal of TGF-beta from these cultures was associated with the appearance of a significant fraction of cycling cells with greater than 4c DNA content, consistent with development of tetraploidy. Results of these studies support a role for TGF-beta in the control of smooth muscle cell growth and suggest that at least one mechanism whereby hypertrophy and hyperploidy may occur in this, as well as other cell types, is by alterations in the response to serum mitogens by potent growth inhibitors such as TGF-beta.

scholarly journals Pathogenic tau disrupts the cellular program that maintains neuronal identity

2021 ◽  
Author(s):  
Adrian Beckmann ◽  
Paulino Ramirez ◽  
Maria Gamez ◽  
William J. Ray ◽  
Bess Frost
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Formation ◽  
Therapeutic Approaches ◽  
Nuclear Pleomorphism ◽  
Mesenchymal Transition ◽  
Neuronal Identity ◽  
Cell Cycle Activation

AbstractNeurons in human Alzheimer’s disease acquire phenotypes that are also present in various cancers, including over-stabilization of the cytoskeleton, nuclear pleomorphism, decondensation of constitutive heterochromatin, and aberrant activation of the cell cycle. Unlike in cancer, in which cell cycle activation drives tumor formation, activation of the cell cycle in post-mitotic neurons is sufficient to induce neuronal death. Multiple lines of evidence suggest that abortive cell cycle activation is a consequence of pathogenic forms of tau, a protein that drives neurodegeneration in Alzheimer’s disease and related “tauopathies.” We have combined network analysis of human Alzheimer’s disease and mouse tauopathy with mechanistic studies in Drosophila to discover that pathogenic forms of tau drive abortive cell cycle activation by disrupting the cellular program that maintains neuronal identity. Mechanistically, we identify Moesin, a prognostic biomarker for cancer and mediator of the epithelial-mesenchymal transition (EMT), as a major effector of tau-induced neurotoxicity. We find that aberrant activation of Moesin in neurons acts through the actin cytoskeleton to dysregulate the cellular program that maintains neuronal identity. Our study identifies mechanistic parallels between tauopathy and cancer and sets the stage for novel therapeutic approaches.

Sign in / Sign up

Export Citation Format

Share Document