Cytotoxic T lymphocyte antigen-2 alpha induces apoptosis of murine T-lymphoma cells and cardiac fibroblasts and is regulated by cAMP/PKA

Zhang, Lingzhi; Yun, Hongruo; Murray, Fiona; Lu, Ruilin; Wang, Lin; Hook, Vivian; Insel, Paul A.

doi:10.1016/j.cellsig.2011.05.014

Cited by 16 publications

(17 citation statements)

References 36 publications

(57 reference statements)

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“…Expression of CTLA-2 is also prominently increased by incubation of WT S49 cells with forskolin (in the presence of IBMX) but only slightly increased in D-S49 cells incubated with either 8-CPT-cAMP or forskolin/IBMX; increases in cAMP do not increase CTLA-2 expression in kin-S49 cells ( • ▶ Fig. 5c) [41].…”

Section: Reviewmentioning

confidence: 89%

Cyclic AMP/PKA-Promoted Apoptosis: Insights from Studies of S49 Lymphoma Cells

et al. 2014

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Increases in cyclic AMP (cAMP) are pro-apoptotic in numerous cell types, but the mechanisms of cAMP-promoted apoptosis are poorly defined. We have used murine S49 T-lymphoma cells as a model to provide insight into these mechanisms. Increases in cAMP in wild-type (WT) S49 cells were first noted to kill these cells in the 1970 s, but only in recent years, it was shown that this occurs by the intrinsic (mitochondria-dependent) apoptotic pathway. The apoptotic response does not occur in protein kinase A-null (kin-) clonal variants of WT S49 cells and thus is mediated by protein kinase A (PKA). A second S49 clonal variant, cAMP-Deathless (D-), has PKA activity but lacks cAMP-promoted apoptosis. Apoptosis in WT S49 cells occurs many hours after cAMP/PKA-promoted G1 cell cycle arrest and involves increased expression of Bim, a pro-apoptotic member of the Bcl-2 (B-cell lymphoma-2) family. This increase in Bim expression does not occur in kin- or D- S49 cells and knockdown of Bim blunts cAMP-mediated apoptosis in WT cells. Cytotoxic T lymphocyte antigen-2 also appears to contribute to cAMP/PKA-promoted apoptosis of S49 cells. Based on time-dependent differences in gene expression between WT, D- and kin- S49 cells following incubation with 8-(4-chlorophenylthio)-cAMP, additional genes and proteins are likely involved in this apoptosis. Studies with S49 cells should reveal further insight regarding the mechanisms of cAMP/PKA-promoted cell death, including the identification of proteins that are targets to enhance (e. g., in cancer) or inhibit (e. g., cardiac failure) apoptosis in response to hormones, neurotransmitters, and drugs.

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Section: Reviewmentioning

confidence: 89%

Cyclic AMP/PKA-Promoted Apoptosis: Insights from Studies of S49 Lymphoma Cells

et al. 2014

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“…5,44 We did not detect changes in these low-abundance proteins, because our analytical procedure favors detection of more abundant ones. S49 cells have large nuclei relative to their amount of cytoplasm; detection of some proteins is thus more difficult than with other cell types.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomics Analysis of the cAMP/Protein Kinase A Signaling Pathway

et al. 2012

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To define the proteins whose expression is regulated by cAMP and protein kinase A (PKA), we used a quantitative proteomics approach in studies of wild-type (WT) and kin- (PKA-null) S49 murine T lymphoma cells. We also compared the impact of endogenous increases in the level of cAMP [by forskolin (Fsk) and the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX)] or by a cAMP analogue (8-CPT-cAMP). We identified 1056 proteins in WT and kin- S49 cells and found that 8-CPT-cAMP and Fsk with IBMX produced differences in protein expression. WT S49 cells had a correlation coefficient of 0.41 between DNA microarray data and the proteomics analysis in cells incubated with 8-CPT-cAMP for 24 h and a correlation coefficient of 0.42 between the DNA microarray data obtained at 6 h and the changes in protein expression after incubation with 8-CPT-cAMP for 24 h. Glutathione reductase (Gsr) had a higher level of basal expression in kin- S49 cells than in WT cells. Consistent with this finding, kin- cells are less sensitive to cell killing and generation of malondialdehyde than are WT cells incubated with H2O2. Cyclic AMP acting via PKA thus has a broad impact on protein expression in mammalian cells, including in the regulation of Gsr and oxidative stress.

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“…Treatment of wild type S49 T cells with the PKA activating cyclic AMP analog, 8-CPT-cAMP, increases the expression of cytotoxic T lymphocyte antigen-2α (CTLA-2α), a cathepsin L-like cysteine protease inhibitor that triggers apoptosis 33 . Treatment of kinase- S49 cells T cells that lack functional PKA, with 8-CPT-cAMP fails to stimulate CTLA-2α expression and apoptosis, indicating that the increase in CTLA-2α in wild type S49 cells is PKA-dependent 34,35 .…”

Section: Paradoxical Effects Of Pka On T Cells Survivalmentioning

confidence: 99%

Regulation of Lymphocyte Function by Adenosine

Linden¹,

Cekic²

2012

ATVB

129

103

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Adenosine regulates the interaction between lymphocytes and the vasculature and is important for controlling lymphocyte trafficking in response to tissue injury or infection. Adenosine can blunt the effects of T cell receptor (TCR) activation primarily by activating adenosine A2A receptors (A2AR) and signaling via cyclic AMP and protein kinase A (PKA). PKA reduces proximal TCR signaling by phosphorylation of C-terminal Src kinase (Csk), nuclear factor of activated T cells (NF-AT) and cyclic AMP response element binding protein (CREB). PKA activation can either enhance or inhibit the survival of T cells depending on the strength and duration of signaling. Inducible enzymes such as CD73 and CD39 regulate adenosine formation and degradation in vivo. The extravasation of lymphocytes through blood vessels is influenced by A2AR-mediated suppression of Intercellular Adhesion Molecule 1 (ICAM) expression on lymphocytes and diminished production of IFNγ and IFNγ-inducible chemokines that are chemotactic to activated lymphocytes. Adenosine also decreases the barrier function of vascular endothelium by activating A2BRs. In sum, adenosine signaling is influenced by tissue inflammation and injury through induction of receptors and enzymes and has generally inhibitory effects on lymphocyte migration into inflamed tissues due to PKA-mediated effects on adhesion molecules, IFNγ production and endothelial barrier function.

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Cytotoxic T lymphocyte antigen-2 alpha induces apoptosis of murine T-lymphoma cells and cardiac fibroblasts and is regulated by cAMP/PKA

Cited by 16 publications

References 36 publications

Cyclic AMP/PKA-Promoted Apoptosis: Insights from Studies of S49 Lymphoma Cells

Cyclic AMP/PKA-Promoted Apoptosis: Insights from Studies of S49 Lymphoma Cells

Quantitative Proteomics Analysis of the cAMP/Protein Kinase A Signaling Pathway

Regulation of Lymphocyte Function by Adenosine

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