scholarly journals Beyond Protein Synthesis; The Multifaceted Roles of Tuberin in Cell Cycle Regulation

2022 ◽  
Vol 9 ◽  
Author(s):  
E. Fidalgo da Silva ◽  
J. Fong ◽  
A. Roye-Azar ◽  
A. Nadi ◽  
C. Drouillard ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Synthesis ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Cell Biology ◽  
Protein Transport ◽  
Critical Role ◽  
Cell Cycle Protein ◽  
Environmental Signals ◽  
Cycle Regulation

The ability of cells to sense diverse environmental signals, including nutrient availability and conditions of stress, is critical for both prokaryotes and eukaryotes to mount an appropriate physiological response. While there is a great deal known about the different biochemical pathways that can detect and relay information from the environment, how these signals are integrated to control progression through the cell cycle is still an expanding area of research. Over the past three decades the proteins Tuberin, Hamartin and TBC1D7 have emerged as a large protein complex called the Tuberous Sclerosis Complex. This complex can integrate a wide variety of environmental signals to control a host of cell biology events including protein synthesis, cell cycle, protein transport, cell adhesion, autophagy, and cell growth. Worldwide efforts have revealed many molecular pathways which alter Tuberin post-translationally to convey messages to these important pathways, with most of the focus being on the regulation over protein synthesis. Herein we review the literature supporting that the Tuberous Sclerosis Complex plays a critical role in integrating environmental signals with the core cell cycle machinery.

scholarly journals p130 And pRb in the Maintenance of Transient Quiescence of Mesenchymal Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Boris Popov ◽  
Nikolai Petrov ◽  
Vladimir Ryabov ◽  
Igor Evsyukov
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Critical Role ◽  
Growth Curves ◽  
State Level ◽  
Gel Shift Assay ◽  
Multipotent Mesenchymal Stem Cells ◽  
Cycle Regulation ◽  
And Control

An effective regulation of quiescence plays a key role in the differentiation, plasticity, and prevention of stem cells from becoming malignant. The state of quiescence is being controlled by the pRb family proteins which show overlapping functions in cell cycle regulation; however, their roles in controlling the proliferation of mesenchymal stem cells (MSCs) remain to be understood. This study investigated the regulation of transient quiescence using growth curves, proliferation assay, the cytometric evaluation of cell cycle, Western blotting, and the electromobility gel shift assay (EMSA) on synchronized MSCs of the C3H10Т1/2 and control cells with different statuses of pRb proteins. It has been found that functional steady-state level of p130 but not pRb plays a critical role for entering, exiting, and maintenance of transient quiescence in multipotent mesenchymal stem cells.

scholarly journals Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2)

2005 ◽  
Vol 388 (3) ◽  
pp. 973-984 ◽  
Author(s):  
Mark ROLFE ◽  
Laura E. McLEOD ◽  
Phillip F. PRATT ◽  
Christopher G. PROUD
Keyword(s):  
Protein Synthesis ◽  
Ribosomal Protein ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mammalian Target Of Rapamycin ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Erk Activation ◽  
Mitogen Activated Protein

The hypertrophic Gq-protein-coupled receptor agonist PE (phenylephrine) activates protein synthesis. We showed previously that activation of protein synthesis by PE requires MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and mTOR (mammalian target of rapamycin). However, it remained unclear whether ERK activation was required and which downstream components were involved in activating mTOR and protein synthesis. Using an adenovirus encoding the MKP3 (MAPK phosphatase 3) to inhibit ERK activity, we demonstrate that ERK is essential for the activation of protein synthesis by PE. Activation and phosphorylation of S6K1 (ribosomal protein S6 kinase 1) and phosphorylation of eIF4E (eukaryotic initiation factor 4E)-binding protein (both are mTOR targets) were also inhibited by MKP3, suggesting that ERK is also required for the activation of mTOR signalling. PE stimulation of cardiomyocytes induced the phosphorylation of TSC2 (tuberous sclerosis complex 2), a negative regulator of mTOR activity. TSC2 was phosphorylated only weakly at Thr1462, but phosphorylated at additional sites within the sequence RXRXX(S/T). This differs from the phosphorylation induced by insulin, indicating that MEK/ERK signalling targets distinct sites in TSC2. This phosphorylation may be mediated by p90RSK (90 kDa ribosomal protein S6K), which is activated by ERK, and appears to involve phosphorylation at Ser1798. Activation of protein synthesis by PE is partially insensitive to the mTOR inhibitor rapamycin. Inhibition of the MAPK-interacting kinases by CGP57380 decreases the phosphorylation of eIF4E and PE-induced protein synthesis. Moreover, CGP57380+rapamycin inhibited protein synthesis to the same extent as blocking ERK activation, suggesting that MAPK-interacting kinases and regulation of mTOR each contribute to the activation of protein synthesis by PE in cardiomyocytes.

scholarly journals Proline responding1 Plays a Critical Role in Regulating General Protein Synthesis and the Cell Cycle in Maize

2014 ◽  
Vol 26 (6) ◽  
pp. 2582-2600 ◽  
Author(s):  
Gang Wang ◽  
Jushan Zhang ◽  
Guifeng Wang ◽  
Xiangyu Fan ◽  
Xin Sun ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Synthesis ◽  
Critical Role ◽  
General Protein Synthesis ◽  
General Protein

scholarly journals Cell cycle regulation in hematopoietic stem cells

2011 ◽  
Vol 195 (5) ◽  
pp. 709-720 ◽  
Author(s):  
Eric M. Pietras ◽  
Matthew R. Warr ◽  
Emmanuelle Passegué
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Cycle Regulation ◽  
Critical Role ◽  
Cellular Damage ◽  
Fetal Life ◽  
Extrinsic Factors ◽  
Hematopoietic Stem ◽  
Cycle Regulation

Hematopoietic stem cells (HSCs) give rise to all lineages of blood cells. Because HSCs must persist for a lifetime, the balance between their proliferation and quiescence is carefully regulated to ensure blood homeostasis while limiting cellular damage. Cell cycle regulation therefore plays a critical role in controlling HSC function during both fetal life and in the adult. The cell cycle activity of HSCs is carefully modulated by a complex interplay between cell-intrinsic mechanisms and cell-extrinsic factors produced by the microenvironment. This fine-tuned regulatory network may become altered with age, leading to aberrant HSC cell cycle regulation, degraded HSC function, and hematological malignancy.

scholarly journals Tuberous sclerosis complex: The critical role of the interventional radiologist in management

2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Puneet Garg ◽  
Anuradha Sharma ◽  
Heena Rajani ◽  
Apratim R. Choudhary ◽  
Rajkumar Meena
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Critical Role ◽  
Interventional Radiologist

scholarly journals Dissecting the Roles of the Tuberin Protein in the Subcellular Localization of the G2/M Cyclin, Cyclin B1

2021 ◽  
Author(s):  
Jessica Dare-Shih ◽  
Adam Pillon ◽  
Jackie Fong ◽  
Elizabeth Fidalgo da Silva ◽  
Lisa Porter
Keyword(s):  
Cell Cycle ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Molecular Mechanisms ◽  
Cyclin B1 ◽  
Nuclear Accumulation ◽  
Benign Tumors ◽  
Tsc2 Gene ◽  
Organ Systems ◽  
Wide Range

Tuberin is a major component of the protein regulatory complex known as the Tuberous Sclerosis Complex and plays a crucial role in cell cycle progression and protein synthesis. Mutations in the Tuberin gene, TSC2, lead to the formation of benign tumors in many organ systems and causes the Tuberous Sclerosis Complex disorder. Genotypes ranging from point mutations to large deletions in the TSC2 gene have been clinically characterized with a wide range of phenotypes from skin tumors to large brain tumors. Our current work investigates the molecular mechanisms behind Tuberin and its ability to regulate the cell cycle through its binding to the G2/M cyclin, Cyclin B1. After creating an early stop codon in a critical region of the Tuberin, our results show the in vitro phenotype that occurs from a truncated Tuberin protein. Herein we demonstrate that this clinically relevant truncated form of Tuberin promotes an increased nuclear accumulation of Cyclin B1 and a subsequent increase in cell proliferation supporting the phenotypic data seen in the clinic with Tuberous Sclerosis Complex patients showing deletions within the TSC2 gene. This data provides an insight into some of the functional and molecular consequences of truncated proteins that are seen in clinical patients.

scholarly journals Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells

2011 ◽  
Vol 193 (4) ◽  
pp. 695-710 ◽  
Author(s):  
Alla Amcheslavsky ◽  
Naoto Ito ◽  
Jin Jiang ◽  
Y. Tony Ip
Keyword(s):  
Stem Cells ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Critical Role ◽  
Intestinal Stem Cells ◽  
Stem Cell Markers ◽  
Disc Cells ◽  
Epithelial Structure ◽  
Rates Of Growth ◽  
Adult Drosophila

Intestinal stem cells (ISCs) in the adult Drosophila melanogaster midgut can respond to damage and support repair. We demonstrate in this paper that the tuberous sclerosis complex (TSC) plays a critical role in balancing ISC growth and division. Previous studies have shown that imaginal disc cells that are mutant for TSC have increased rates of growth and division. However, we report in this paper that loss of TSC in the adult Drosophila midgut results in the formation of much larger ISCs that have halted cell division. These mutant ISCs expressed proper stem cell markers, did not differentiate, and had defects in multiple steps of the cell cycle. Slowing the growth by feeding rapamycin or reducing Myc was sufficient to rescue the division defect. The TSC mutant guts had a thinner epithelial structure than wild-type tissues, and the mutant flies were more susceptible to tissue damage. Therefore, we have uncovered a context-dependent phenotype of TSC mutants in adult ISCs, such that the excessive growth leads to inhibition of division.

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