scholarly journals cAMP antagonizes interleukin 2-promoted T-cell cycle progression at a discrete point in early G1.

1988 ◽  
Vol 85 (16) ◽  
pp. 6072-6076 ◽  
Author(s):  
K. W. Johnson ◽  
B. H. Davis ◽  
K. A. Smith
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Cycle Progression ◽  
Interleukin 2 ◽  
Discrete Point ◽  
Cycle Progression

scholarly journals p70s6k Integrates Phosphatidylinositol 3-Kinase and Rapamycin-Regulated Signals for E2F Regulation in T Lymphocytes

1999 ◽  
Vol 19 (7) ◽  
pp. 4729-4738 ◽  
Author(s):  
Paul Brennan ◽  
J. W. Babbage ◽  
G. Thomas ◽  
Doreen Cantrell
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Cycle Progression ◽  
Transcriptional Activity ◽  
Interleukin 2 ◽  
Cell Cycle Checkpoint ◽  
Phosphatidylinositol 3 Kinase ◽  
Cycle Progression ◽  
Phosphatidylinositol 3

ABSTRACT In T lymphocytes, the hematopoietic cytokine interleukin-2 (IL-2) uses phosphatidylinositol 3-kinase (PI 3-kinase)-induced signaling pathways to regulate E2F transcriptional activity, a critical cell cycle checkpoint. PI 3-kinase also regulates the activity of p70s6k, the 40S ribosomal protein S6 kinase, a response that is abrogated by the macrolide rapamycin. This immunosuppressive drug is known to prevent T-cell proliferation, but the precise point at which rapamycin regulates T-cell cycle progression has yet to be elucidated. Moreover, the effects of rapamycin on, and the role of p70s6k in, IL-2 and PI 3-kinase activation of E2Fs have not been characterized. Our present results show that IL-2- and PI 3-kinase-induced pathways for the regulation of E2F transcriptional activity include both rapamycin-resistant and rapamycin-sensitive components. Expression of a rapamycin-resistant mutant of p70s6k in T cells could restore rapamycin-suppressed E2F responses. Thus, the rapamycin-controlled processes involved in E2F regulation appear to be mediated by p70s6k. However, the rapamycin-resistant p70s6k could not rescue rapamycin inhibition of T-cell cycle entry, consistent with the involvement of additional, rapamycin-sensitive pathways in the control of T-cell cycle progression. The present results thus show that p70s6k is able to regulate E2F transcriptional activity and provide direct evidence for the first time for a link between IL-2 receptors, PI 3-kinase, and p70s6k that regulates a crucial G1 checkpoint in T lymphocytes.

Transforming growth factors beta slow down cell-cycle progression in a murine interleukin-2 dependent T-cell line

1989 ◽  
Vol 141 (1) ◽  
pp. 65-73 ◽  
Author(s):  
Michael Stoeck ◽  
Sylvia Miescher ◽  
H. Robson MacDonald ◽  
Vladimir Von Fliedner
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
T Cell ◽  
Cell Line ◽  
Cell Cycle Progression ◽  
Interleukin 2 ◽  
Transforming Growth Factors ◽  
Cycle Progression

scholarly journals Interleukin-2 expression in human carcinoma cell lines and its role in cell cycle progression

Oncogene ◽  
2000 ◽  
Vol 19 (4) ◽  
pp. 514-525 ◽  
Author(s):  
Torsten E Reichert ◽  
Shigeki Nagashima ◽  
Yoshiro Kashii ◽  
Joanna Stanson ◽  
Gui Gao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Carcinoma Cell ◽  
Interleukin 2 ◽  
Cycle Progression ◽  
Human Carcinoma ◽  
Carcinoma Cell Lines ◽  
Human Carcinoma Cell

scholarly journals Molecular cloning of a novel mitogen-inducible nuclear protein with a Ran GTPase-activating domain that affects cell cycle progression.

1995 ◽  
Vol 15 (1) ◽  
pp. 552-560 ◽  
Author(s):  
M Hattori ◽  
N Tsukamoto ◽  
M S Nur-e-Kamal ◽  
B Rubinfeld ◽  
K Iwai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Nuclear Protein ◽  
Interleukin 2 ◽  
Quiescent State ◽  
Cycle Progression ◽  
Ran Gtpase ◽  
G0 Phase ◽  
Nih 3T3

We have cloned a novel cDNA (Spa-1) which is little expressed in the quiescent state but induced in the interleukin 2-stimulated cycling state of an interleukin 2-responsive murine lymphoid cell line by differential hybridization. Spa-1 mRNA (3.5 kb) was induced in normal lymphocytes following various types of mitogenic stimulation. In normal organs it is preferentially expressed in both fetal and adult lymphohematopoietic tissues. A Spa-1-encoded protein of 68 kDa is localized mostly in the nucleus. Its N-terminal domain is highly homologous to a human Rap1 GTPase-activating protein (GAP), and a fusion protein of this domain (SpanN) indeed exhibited GAP activity for Rap1/Rsr1 but not for Ras or Rho in vitro. Unlike the human Rap1 GAP, however, SpanN also exhibited GAP activity for Ran, so far the only known Ras-related GTPase in the nucleus. In the presence of serum, stable Spa-1 cDNA transfectants of NIH 3T3 cells (NIH/Spa-1) hardly overexpressed Spa-1 (p68), and they grew as normally as did the parental cells. When NIH/Spa-1 cells were serum starved to be arrested in the G1/G0 phase of the cell cycle, however, they, unlike the control cells, exhibited progressive Spa-1 p68 accumulation, and following the addition of serum they showed cell death resembling mitotic catastrophes of the S phase during cell cycle progression. The results indicate that the novel nuclear protein Spa-1, with a potentially active Ran GAP domain, severely hampers the mitogen-induced cell cycle progression when abnormally and/or prematurely expressed. Functions of the Spa-1 protein and its regulation are discussed in the context of its possible interaction with the Ran/RCC-1 system, which is involved in the coordinated nuclear functions, including cell division.

Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27kip1

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1524-1531 ◽  
Author(s):  
Joao T. Barata ◽  
Angelo A. Cardoso ◽  
Lee M. Nadler ◽  
Vassiliki A. Boussiotis
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Cycle Progression ◽  
Lymphoblastic Leukemia ◽  
Cyclin Dependent Kinase ◽  
Malignant Cells ◽  
Cycle Progression ◽  
Interleukin 7 ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Immature Thymocytes

In normal T-cell development interleukin-7 (IL-7) functions as an antiapoptotic factor by regulating bcl-2 expression in immature thymocytes and mature T cells. Similar to what occurs in normal immature thymocytes, prevention of spontaneous apoptosis by IL-7 in precursor T-cell acute lymphoblastic leukemia (T-ALL) cells correlates with up-regulation of bcl-2. IL-7 is also implicated in leukemogenesis because IL-7 transgenic mice develop lymphoid malignancies, suggesting that IL-7 may regulate the generation and expansion of malignant cells. This study shows that in the presence of IL-7, T-ALL cells not only up-regulated bcl-2 expression and escaped apoptosis but also progressed in the cell cycle, resulting in sequential induction of cyclin D2 and cyclin A. Down-regulation of p27kip1 was mandatory for IL-7–mediated cell cycle progression and temporally coincided with activation of cyclin-dependent kinase (cdk)4 and cdk2 and hyperphosphorylation of Rb. Strikingly, forced expression of p27kip1 in T-ALL cells not only prevented cell cycle progression but also reversed IL-7–mediated up-regulation of bcl-2 and promotion of viability. These results show for the first time that a causative link between IL-7–mediated proliferation and p27kip1 down-regulation exists in malignant T cells. Moreover, these results suggest that p27kip1 may function as a tumor suppressor gene not only because it is a negative regulator of cell cycle progression but also because it is associated with induction of apoptosis of primary malignant cells.

scholarly journals HCV core/gC1qR interaction arrests T cell cycle progression through stabilization of the cell cycle inhibitor p27Kip1

Virology ◽  
2003 ◽  
Vol 314 (1) ◽  
pp. 271-282 ◽  
Author(s):  
Zhi Qiang Yao ◽  
Audrey Eisen-Vandervelde ◽  
Suma Ray ◽  
Young S Hahn
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cell Cycle Inhibitor

OSI-027, a Dual TORC1/TORC2 Inhibitor, Induces Bim- and Puma-Mediated Apoptosis In Lymphoid Malignancy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 970-970 ◽  
Author(s):  
Andrea E. Wahner Hendrickson ◽  
Mamta Gupta ◽  
Seongseok Yun ◽  
Jennifer C. Shing ◽  
Paula A. Schneider ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Cycle Progression ◽  
Mitochondrial Pathway ◽  
Lymphoid Cells ◽  
Jurkat Cells ◽  
Lymphoid Malignancy ◽  
Cycle Progression ◽  
Advisory Boards ◽  
Wide Range

Abstract Abstract 970 The mammalian target of rapamycin, mTOR, is a highly conserved serine/threonine kinase known to play a role in regulating mRNA translation, cell cycle progression, cell proliferation and apoptosis. As a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, mTOR is a component of two distinct complexes, TORC1 and TORC2. While TORC1 facilitates cell cycle progression from G1 into S phase by phosphorylating p70S6 kinase and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), TORC2 catalyzes the activating phosphorylation of Akt on Ser473, providing a feedback loop for further activation of mTOR. Phase II trials have shown activity of the TORC1-selective inhibitor rapamycin and its analogs in a wide range of lymphoma subtypes. The purpose of this study was to evaluate the anti-proliferative and pro-apoptotic effects of the dual TORC1/TORC2 inhibitor OSI-027 in human neoplastic lymphoid cells in vitro. MTS assays demonstrated that OSI-027 inhibited proliferation in a wide range of lymphoid lines, including SeAx (Sezary syndrome), DoHH2 (large cell lymphoma), RL (follicular lymphoma) and Jurkat (T cell ALL), as well as clinical lymphoma and T cell ALL samples, with IC50 values ranging from 0.078 to 10 μM. Propidium iodide staining followed by flow cytometry for subdiploid cells revealed induction of apoptosis within 48 h of treatment with OSI-027 (but not rapamycin) in SeAx, DoHH2, and Jurkat cells. Examination of Jurkat variants with alterations in key proteins involved in the death receptor versus mitochondrial pathway revealed diminished apoptotic responses to OSI-027 when Bcl-2 was overexpressed or caspase 9 was silenced, indicating involvement of the mitochondrial pathway. Immunoblotting for Bcl-2 family members revealed upregulation of Bim and Puma after a 48-hour exposure to OSI-027 but not rapamycin. This upregulation was also seen at the mRNA level, with a 12- to 20-fold increase in Puma mRNA and 4- to 12-fold induction of Bim mRNA. Small interfering RNA (siRNA)-mediated knockdown of Bim and Puma significantly diminished the apoptotic response to OSI-027. Because the Foxo3a transcription factor has been implicated in Bim and Puma expression and is known to be activated when Akt is inhibited, we next examined whether Bim and Puma induction was Foxo3a-dependent. Luciferase reporter assays showed that OSI-027 activated the full-length Puma and Bim promoters and that this activation was diminished when the Foxo3a binding sites were deleted or mutated. In addition, OSI-027 induced nuclear translocation of Foxo3a, while Foxo3a siRNA diminished OSI-027-induced apoptosis in Jurkat cells. Collectively, these results indicate that OSI-027 inhibits proliferation and induces apoptosis in a wide range of neoplastic lymphoid cells through a process that involves Foxo3a-mediated upregulation of Bim and Puma. These results also suggest that dual inhibition of TORC1 and TORC2 may be an effective treatment strategy in lymphoid malignancy. Disclosures: Barr: OSI Pharmaceuticals: Employment. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

PD-1 Signals Inhibit Cell Cycle Progression by Mediating Upregulation of Both KIP and INK Family of Cdk Inhibitors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 585-585
Author(s):  
Julia Brown ◽  
Nikolaos Patsoukis ◽  
Vassiliki A Boussiotis
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Cdk Inhibitors ◽  
Cycle Progression ◽  
Smad3 Phosphorylation ◽  
Cells Cultured

Abstract Abstract 585 The PD-1 pathway plays a critical role in the inhibition of T cell activation and the maintenance of T cell tolerance. PD-1 is expressed on activated T cells and limits T cell clonal expansion and effector function upon engagement with its ligands PD-L1 and PD-L2. PD-1 signals are vital for inhibition of autoimmunity whereas PD-1 ligation by PD-L1 and PD-L2 expressed on malignant cells has a detrimental effect on tumor-specific immunity. Furthermore, PD-1 signals result in T cell exhaustion in several chronic viral infections. The mechanism via which PD-1 signals mediate inhibition of T cell expansion is currently poorly understood. Here, we sought to determine the effects of PD-1 signals on mechanistic regulation of cell cycle progression mediated via TCR/CD3 and CD28 in primary human CD4+ T cells using anti-CD3/CD28 with or without agonist anti-PD-1 mAb conjugated to magnetic beads. Cell cycle analysis by ethynyl-deoxyuridine incorporation revealed that PD-1 induced blockade of cell cycle progression at the early G1 phase. To determine the molecular mechanisms underlying the blocked cell cycle progression we examined the expression and activation of cyclins and cdks and the regulation of cdk inhibitors that counterbalance the enzymatic activation of cyclin/cdk holoenzyme complexes. Our studies revealed that PD-1 mediated signals inhibited upregulation of Skp2, the SCF ubiquitin ligase that leads p27kip1 cdk inhibitor to ubiquitin-dependent degradation, and resulted in accumulation of p27kip1. Expression of cyclin E that is induced at the G1/S phase transition, and cyclin A that is synthesized during the S phase of the cell cycle, was dramatically reduced in the presence of PD-1 signaling. Strikingly, although expression of cdk4 and cdk2 was comparable between cells cultured in the presence or in the absence of PD-1, cdk2 enzymatic activation was significantly reduced in the presence of PD-1 signaling. Smad3 is a novel critical cdk substrate. Maximum cdk-mediated Smad3 phosphorylation occurs at the G1/S phase junction and requires activation of cdk2. Phosphorylation by cdk antagonizes TGF-β-induced transcriptional activity and antiproliferative function of Smad3 whereas impaired phosphorylation on the cdk-specific sites renders Smad3 more effective in executing its antiproliferative function. Based on those findings, we examined the effects of PD-1 signaling on Smad3 phosphorylation on cdk-specific and TGF-β-specific sites using site-specific phospho-Smad3 antibodies. Compared to anti-CD3/CD28 alone, culture in the presence of PD-1 induced impaired cdk2 activity, reduced levels of Smad3 phosphorylation on the cdk-specific sites and increased Smad3 phophorylation on the TGF-b-specific site. To determine whether the differential phosphorylation of Smad3 might differentially regulate Smad3 transcriptional activity in CD4+ T cells cultured in the presence versus the absence of PD-1, we examined expression of the INK family cdk4/6 inhibitor p15, a known downstream transcriptional target of Smad3. Expression of p15 was upregulated in CD4+ T cells cultured in the presence of PD-1 but not in cells cultured in the presence of CD3/CD28-coated beads alone. These results indicate that PD-1 signals inhibit cell cycle progression by mediating upregulation of both KIP and INK family of cdk inhibitors and Smad3 is a critical component of this mechanism, regulating blockade at the early G1 phase. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document