scholarly journals Silymarin Inhibits Cell Cycle Progression and mTOR Activity in Activated Human T Cells: Therapeutic Implications for Autoimmune Diseases

2012 ◽  
Vol 112 (4) ◽  
pp. 251-256 ◽  
Author(s):  
Marjan Gharagozloo ◽  
Elahe N. Javid ◽  
Abbas Rezaei ◽  
Kazem Mousavizadeh
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Autoimmune Diseases ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Therapeutic Implications ◽  
Human T Cells ◽  
Mtor Activity

Systems Biology Analysis of Human Primary T Cells Identifies SAP145 as Rate Limiting for the G1→S Phase Transition.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3350-3350
Author(s):  
Stephen J. Orr ◽  
Rong Wang ◽  
Nicholas C. Lea ◽  
Constantinos Chronis ◽  
Arun K. Ramani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Systems Biology ◽  
Rna Splicing ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Phase Cell ◽  
Cycle Progression ◽  
Human T Cells ◽  
Rate Limiting

Abstract We identified a G0→G1 commitment point in primary human T cells that controls entry into the cell cycle from quiescence. We demonstrated proof of principle that cellular pathways regulating cell cycle progression and effector functions that normally coincide during CD3/CD28 stimulation can be uncoupled experimentally. We have now used systems biology approaches to identify nuclear protein networks in primary human T cells that are regulated during the transition from quiescence into the cell cycle (G0→G1→S-phase). First we sequenced proteins that became bound to chromatin & nuclear matrix in G1 but were not bound in G0 and vice versa by mass spectrometry. Bioinformatic analysis identified 76 proteins specifically bound in G0 not G1 and 254 bound in G1 not G0. 179 of the 254 proteins bound in G1 not G0 (i.e. dynamic protein changes) were mapped to the 55,000 human protein interaction dataset. These are involved in numerous cellular functions, including epigenetics, transcription, RNA splicing & transport, and others. Cell cycle regulated chromatin/matrix binding of a subset was verified by western blotting (2/2 bound in G0 not G1 and 22/23 bound in G1 not G0). One of the proteins induced and bound in G1 was SAP145 (SF3B2). This is a component of the ubiquitous SF3b RNA splicing complex, involved in both major (U2-type) and minor (U12-type) spliceosomes. Since SAP145 is induced during G1 we investigated whether there was a role for SAP145 in regulating cell cycle progression. T cells depleted of SAP145 by siRNA enter G1 from G0 but progress poorly through S phase and die, probably by apoptosis. The same occurs if another component of the SF3B complex, SAP49 (SF3B4) is depleted with siRNA, indicating that the effect is due to depleting the complex rather than the individual SF3B protein. Proteins that are induced during G1 by CD3/CD28 stimulation e.g. cyclin D3, Cdc6 and cdc2 are produced normally when SAP145 is depleted, suggesting that their pre-mRNAs are spliced normally. In contrast, the expression of p107 and cyclin A2 are reduced markedly when SAP145 is depleted. Therefore, a systems biology approach to analysing cell cycle transitions identifies the splicing protein, SAP145 as rate-limiting for the G1 →S phase cell cycle transition but not for the transition from G0→G1.

CELL CYCLE PROGRESSION OF HUMAN T CELLS BY HTLV-I TAX

1999 ◽  
Vol 20 (4) ◽  
pp. A32
Author(s):  
Kiyoshi Ohtani ◽  
Ritsuko Iwanaga ◽  
Yong-Ping Huang ◽  
Masataka Nakamura
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Human T Cells

scholarly journals CD28 Costimulation Mediates Down-Regulation of p27kip1and Cell Cycle Progression by Activation of the PI3K/PKB Signaling Pathway in Primary Human T Cells

2002 ◽  
Vol 168 (6) ◽  
pp. 2729-2736 ◽  
Author(s):  
Leonard J. Appleman ◽  
Andre A. F. L. van Puijenbroek ◽  
Kirstin M. Shu ◽  
Lee M. Nadler ◽  
Vassiliki A. Boussiotis
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Signaling Pathway ◽  
Cell Cycle Progression ◽  
Down Regulation ◽  
Cycle Progression ◽  
Cd28 Costimulation ◽  
Human T Cells

scholarly journals Effects of Guanine Nucleotide Depletion on Cell Cycle Progression in Human T Lymphocytes

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2896-2904 ◽  
Author(s):  
Josée Laliberté ◽  
Ann Yee ◽  
Yue Xiong ◽  
Beverly S. Mitchell
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Lymphocytes ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Guanine Nucleotides ◽  
Erythroid Cell ◽  
Guanine Nucleotide ◽  
Cycle Progression ◽  
Human T Lymphocytes

Depletion of guanine nucleotide pools after inhibition of inosine monophosphate dehydrogenase (IMPDH) potently inhibits DNA synthesis by arresting cells in G1 and has been shown to induce the differentiation of cultured myeloid and erythroid cell lines, as well as chronic granulocytic leukemic cells after blast transformation. Inhibitors of IMPDH are also highly effective as immunosuppressive agents. The mechanism underlying these pleiotropic effects of depletion of guanine nucleotides is unknown. We have examined the effects of mycophenolic acid (MPA), a potent IMPDH inhibitor, on the cell cycle progression of activated normal human T lymphocytes. MPA treatment resulted in the inhibition of pRb phosphorylation and cell entry into S phase. The expression of cyclin D3, a major component of the cyclin-dependent kinase (CDK) activity required for pRb phosphorylation, was completely abrogated by MPA treatment of T cells activated by interleukin-2 (IL-2) and leucoagglutinin (PHA-L), whereas the expression of cyclin D2, CDK6, and CDK4 was more mildly attenuated. The direct kinase activity of a complex immunoprecipitated with anti-CDK6 antibody was also inhibited. In addition, MPA prevented the IL-2–induced elimination of p27Kip1, a CDK inhibitor, and resulted in the retention of high levels of p27Kip1 in IL-2/PHA-L–treated T cells bound to CDK2. These results indicate that inhibition of the de novo synthesis of guanine nucleotides blocks the transition of normal peripheral blood T lymphocytes from G0 to S phase in early- to mid-G1 and that this cell cycle arrest results from inhibition of the induction of cyclin D/CDK6 kinase and the elimination of p27Kip1 inhibitory activity.

Cell Cycle Progression Out of G1 Sensitizes Primary-Cultured Nontransformed T Cells to TCR-Mediated Apoptosis

1996 ◽  
Vol 170 (2) ◽  
pp. 260-273 ◽  
Author(s):  
Laszlo G. Radvanyi ◽  
Yufang Shi ◽  
Gordon B. Mills ◽  
Richard G. Miller
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cell Cycle Progression ◽  
Cycle Progression

Thymic atrophy in murine acute graft-versus-host disease is effected by impaired cell cycle progression of host pro-T and pre-T cells

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 347-354 ◽  
Author(s):  
Werner Krenger ◽  
Simona Rossi ◽  
Luca Piali ◽  
Georg A. Holländer
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Cell Cycle Progression ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cycle Progression ◽  
Thymic Atrophy ◽  
Graft Versus Host

Abstract Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone marrow transplantation and is also dependent on the reestablishment of normal thymic structure and function. Graft-versus-host disease (GVHD), however, exacerbates posttransplant immunodeficiency through a deleterious effect on thymic function. To investigate the mechanisms of GVHD-mediated thymic disease, 2 murine parent→F1transplantation models of acute and chronic GVHD, respectively, were studied. Acute GVHD was associated with changes in thymic architecture and a reduction in cellularity mainly because of the decrease in CD4+CD8+, or double-positive (DP) thymocytes, to less than 15% of values found in mice without GVHD. Simultaneously, mature donor-derived T cells expanded in the confines of the allogeneic thymic microenvironment, leading to local inflammation. Through analysis of in vivo cell proliferation, we demonstrated that the ensuing depletion of DP thymocytes was secondary to a decreased commitment of resident pro-T and pre-T cells to enter the cell cycle. Moreover, DP cells themselves showed altered proliferative capacities in the presence of acute GVHD. These findings suggested that thymic atrophy in acute GVHD is effected by impaired cellular proliferation of immature host thymocytes and that the failure of these cells to enter the cell cycle is dependent on an interferon (IFN)-γ–driven immune response. In contrast, interleukin-4–driven chronic GVHD was not accompanied by a sustained thymic infiltration of donor T cells. Consequently, there was a lack of apparent structural changes, a restricted in situ transcription of inflammatory cytokines, and a virtually unchanged cell cycle progression in vivo.

scholarly journals Rapid proliferation of activated lymph node CD4+ T cells is achieved by greatly curtailing the duration of gap phases in cell cycle progression

2014 ◽  
Vol 19 (4) ◽  
Author(s):  
Takuya Mishima ◽  
Shoko Toda ◽  
Yoshiaki Ando ◽  
Tsukasa Matsunaga ◽  
Manabu Inobe
Keyword(s):  
Cell Cycle ◽  
Immune Response ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cycle Times ◽  
Peripheral T Cells ◽  
G0 Phase

AbstractPeripheral T cells are in G0 phase and do not proliferate. When they encounter an antigen, they enter the cell cycle and proliferate in order to initiate an active immune response. Here, we have determined the first two cell cycle times of a leading population of CD4+ T cells stimulated by PMA plus ionomycin in vitro. The first cell cycle began around 10 h after stimulation and took approximately 16 h. Surprisingly, the second cell cycle was extremely rapid and required only 6 h. T cells might have a unique regulatory mechanism to compensate for the shortage of the gap phases in cell cycle progression. This unique feature might be a basis for a quick immune response against pathogens, as it maximizes the rate of proliferation.

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