Dataset Information

Interaction between TCL1 and Epac1 in the activation of Akt kinases in plasma membranes and nuclei of 8-CPT-2-O-Me-cAMP-stimulated macrophages.

ABSTRACT: Epac1 is a cAMP-stimulated guanine exchange factor that activates Rap1. The protein product of the T cell leukemia 1 (TCL1) proto-oncogene binds to Akt enhancing its kinase activity. TCL1 and Epac promote cellular proliferation because of their activating effects on Akt. Employing macrophages, we have studied the mechanisms whereby these proteins function in the regulation of Akt kinase activity. Cells were treated with 8-CPT-2-O-Me-cAMP, a cAMP analog which acts selectively and specifically via Epac1. Epac1 co-immunoprecipitated with TCL1 in plasma membrane and nuclear fractions of 8-CPT-2-O-Me-cAMP-stimulated macrophages. Interaction of TCL1 and Epac1 was also observed in a [125I]GST-Epac1 pulldown assay. A two-threefold increase in Akt Thr-308 and Akt Ser-473 protein kinase activities and their phosphoprotein levels was observed in TCL1 immunoprecipitates of plasma membranes and nuclei of the treated cells. Elevated Akt Thr-308 protein kinase activity and its phosphoprotein levels were significantly reduced in TCL1 immunoprecipitates of plasma membranes of 8-CPT-2-O-Me-cAMP-treated cells where Epac1 gene expression was silenced. In contrast, Akt Ser-473 protein kinase activity and its phosphoprotein levels were reduced only in plasma membranes. Our studies suggest that a ternary complex of TCL1, Epac1, and Akt forms in activated macrophages both promoting Akt activation and regulating intracellular distribution of Akt.

SUBMITTER: Misra UK

PROVIDER: S-EPMC2259443 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Interaction between TCL1 and Epac1 in the activation of Akt kinases in plasma membranes and nuclei of 8-CPT-2-O-Me-cAMP-stimulated macrophages.

Misra Uma K UK Kaczowka Steven J SJ Pizzo Salvatore V SV

Cellular signalling 20071012 1

Epac1 is a cAMP-stimulated guanine exchange factor that activates Rap1. The protein product of the T cell leukemia 1 (TCL1) proto-oncogene binds to Akt enhancing its kinase activity. TCL1 and Epac promote cellular proliferation because of their activating effects on Akt. Employing macrophages, we have studied the mechanisms whereby these proteins function in the regulation of Akt kinase activity. Cells were treated with 8-CPT-2-O-Me-cAMP, a cAMP analog which acts selectively and specifically via ...[more]

PMID: 17993260

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Project description:CPT-11 is a first-line chemotherapeutic agent for the treatment of colorectal cancer in clinic. Previous studies including ours have demonstrated that CPT-11 is, however, toxic to the intestinal epithelium and resident peritoneal macrophages. By interacting with B1 cells, the resident peritoneal macrophages play critical roles in the maintenance of gastrointestinal homeostasis. It remains therefore elusive whether these peritoneal innate immune cells could be rebuilt spontaneously or artificially after being impaired by CPT-11 administration. In this study, we found that mouse resident peritoneal macrophages, namely the large peritoneal macrophages (LPMs) with a CD11b+F4/80hiGATA6+ phenotype, and B1 (CD19+CD23-) cells were depleted by intraperitoneal (i.p.) CPT-11 treatment within 1 week, but reappeared from day 14 after CPT-11 treatment. However, the recovery processes of these innate immune cells were slow, as their counts could not be fully recovered even 2 months later, when compared with that of vehicle-treated control group. Interestingly, in the peritoneal cavity of the mice treated with CPT-11, the cell counts of LPMs and B1 cells were significantly increased after adoptive transfer with syngeneic peritoneal exudate cells (PECs) from healthy mice. Adoptive transfer with bone marrow cells also slightly increased, although not significantly, the cell counts of LPMs and B1 cells in CPT-11-treated mice. The survival rate of bacterial infected mice was significantly reduced by i.p. CPT-11 treatment in comparison with vehicle-treated or untreated control groups. Besides, oral administration of CPT-11 also had a delayed toxicity on the resident peritoneal macrophages. Our results suggest that CPT-11 has prolonged deleterious effects on peritoneal innate immune cells but adoptive transfer with PECs may accelerate their recovery processes, highlighting the potential of adoptive cell transfer as an avenue to counteract the adverse effects of this chemotherapeutic agent.

Dataset Information

Interaction between TCL1 and Epac1 in the activation of Akt kinases in plasma membranes and nuclei of 8-CPT-2-O-Me-cAMP-stimulated macrophages.

Publications

Interaction between TCL1 and Epac1 in the activation of Akt kinases in plasma membranes and nuclei of 8-CPT-2-O-Me-cAMP-stimulated macrophages.

Similar Datasets

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