Rise and Fall of Cyclic AMP Required for Onset of Lymphocyte DNA Synthesis

Wang, Ting‐Chung; Sheppard, J. R.; Foker, John E.

doi:10.1126/science.208147

Cited by 147 publications

(46 citation statements)

References 36 publications

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“…These alternative activation pathways may be extremely important in lymphocytes, since it is well known that cAMP or analogs of cAMP suppress T-lymphocyte proliferation (32). Also, the suppression by cAMP appears to be mediated by inhibiting IL-2-driven T-cell activation at a discrete point in G, (31,75).…”

Section: Discussionmentioning

confidence: 99%

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

Huang¹,

Shipman-Appasamy²,

Orten³

et al. 1994

Mol. Cell. Biol.

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The proliferating-cell nuclear antigen (PCNA) gene encodes an auxiliary factor of DNA polymerase delta and functions in DNA replication during S phase. It is expressed at much higher levels in proliferating cells than in quiescent cells. We have studied the regulatory role of the 5'-flanking sequence of the murine PCNA gene in interleukin 2 (IL-2)-responsive cloned T cells (L2). Analysis of a set of deletion constructs in transient transfection assays measuring heterologous reporter gene (luciferase) activity demonstrated that the 182-bp 5'-flanking region provides full promoter activity in IL-2-stimulated L2 cells. While many elements contribute to PCNA promoter strength in IL-2-stimulated cells, the largest decrease in activity occurred with deletion of the tandem CRE (cyclic AMP response element) binding sites located at nucleotides -37 to -52. With a gel mobility shift assay, several IL-2-inducible DNA-protein complexes were detected, including CREB (CREbinding) and ATFI (activating transcription factor) proteins that are specific for the PCNA-CRE sequence.Methylation interference analysis confirmed specific binding of these proteins to the CRE sites. Mutation at the PCNA-CRE motif abolishes IL-2-inducible binding and reduces substantially PCNA promoter activity.These results indicate that IL-2-stimulated PCNA transcription may be partially mediated by these CRE-binding proteins.The activation of antigen-specific T lymphocytes from Go to S phase usually requires several signals. Initially, antigen interacts with the T-cell antigen receptor, which leads to the transition from Go to GI and the expression of interleukin 2 (IL-2) receptor and lymphokines including IL-2. Further GI progression requires additional signals provided by the interaction of IL-2 with its high-affinity receptor, which results in the expression of genes related to G, activation, and binding of prolactin to its receptor, which results in entry into S phase and DNA replication (11,14,35,38,67).One of the genes expressed during IL-2-driven G, progression is proliferating-cell nuclear antigen (PCNA) (49, 69). PCNA was originally described as a proliferation-associated nuclear antigen that was thought to be expressed in a cellcycle-specific manner (8,47). While PCNA is an auxiliary protein for DNA polymerase delta (leading-strand polymerase) (9, 59) and PCNA-associated immunofluorescence closely parallels [3H]thymidine incorporation during cell cycle progression (42), synthesis and expression of PCNA can be detected in all phases of the cell cycle (G11SG2/M) in proliferating cells, suggesting that the protein is easily extractable when it is not associated with the polymerase (10, 49). Beach and coworkers showed recently that D-type cyclins can directly interact with PCNA and suggested this interaction as one possible mechanism by which the cell cycle machinery could * Corresponding author. Present address:

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Section: Discussionmentioning

confidence: 99%

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

Huang¹,

Shipman-Appasamy²,

Orten³

et al. 1994

Mol. Cell. Biol.

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“…Increased cAMP levels are thought to be critical for the entry of lymphocytes into the S-phase and for the subsequent DNA synthesis [30][31][32]. TBTC caused a concentration-dependent inhibition of the PGEl-induced cAMP production.…”

Section: Discussionmentioning

confidence: 99%

Effects of tri-n-butyltin chloride on energy metabolism, macromolecular synthesis, precursor uptake and cyclic AMP production in isolated rat thymocytes

Snoeij

Punt

Penninks

et al. 1986

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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The inhibitor of oxidative phosphorylation tri-n-butyltin chloride (TBTC) causes membrane damage and disintegration of isolated rat thymocytes at concentrations higher than 1 ixM. From a concentration of 0.1 I~M, TBTC disturbs energy metabolism as indicated by an increase in methylglucose uptake, glucose consumption and lactate production and by a decrease in cellular ATP levels. Over the same TBTC concentration range, the incorporation of DNA, RNA and protein precursors are markedly reduced. Moreover the production of cyclic AMP upon stimulation of the cells with prostaglandin E 1 is effectively inhibited. These effects cannot be explained by an inhibition of nucleoside kinase activity, amino acid uptake or adenylate cyclase activity. The effects of TBTC on macromolecular synthesis and cyclic AMP production are possibly due to a disturbance of the cellular energy state.

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“…In contrast, loss of GLP-1R signalling in primary thymocytes resulted in a significantly diminished proliferation response upon ConA and PMA plus ionomycin stimulation, but there was no difference on the proliferative response when thymocytes were stimulated with anti-CD-3 and anti-CD-3 plus anti-CD-28 activation. Stimulation of T cells with ConA is dependent on changes in cellular cAMP [36,37]. Hence it is possible that GLP-1R activation has an additive effect on cAMP accumulation following activation with ConA, and the absence of this additive effect, as is the case in immune cells lacking functional GLP-1R, results in a defective proliferative response.…”

Section: And 5)mentioning

confidence: 99%

Glucagon-like peptide-1 receptor signalling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T cells

et al. 2010

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Rise and Fall of Cyclic AMP Required for Onset of Lymphocyte DNA Synthesis

Cited by 147 publications

References 36 publications

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

Effects of tri-n-butyltin chloride on energy metabolism, macromolecular synthesis, precursor uptake and cyclic AMP production in isolated rat thymocytes

Glucagon-like peptide-1 receptor signalling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T cells

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