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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2661-2667. Prepublished online as a Blood First Edition Paper on November 13, 2003; DOI 10.1182/blood-2003-06-2154. This Article Full Text (PDF) All Versions of this Article: 2003-06-2154v1 103/7/2661    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tiwari, S. Articles by Lerner, A. Search for Related Content PubMed PubMed Citation Articles by Tiwari, S. Articles by Lerner, A. Social Bookmarking                   What's this? Submitted June 27, 2003 Accepted November 3, 2003 Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1 but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis Sanjay Tiwari, Kyriacos Felekkis, Eun-Yi Moon, Amanda Flies, David H Sherr, and Adam Lerner* Department of Medicine, Boston Medical Center, Boston, MA, USA; Department of Pathology, Boston University School of Medicine, Boston, MA, USA Department of Microbiology, Boston University School of Medicine, Boston, MA, USA Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA Department of Biochemistry, Korea Research Institute of Bioscience and Biotechnology, Daejeon City, South Korea * Corresponding author; email: alerner{at}medicine.bu.edu. Type 4 cyclic AMP phosphodiesterase (PDE4) inhibitors and other agents that raise intracellular cAMP levels induce apoptosis in B cell chronic lymphocytic leukemia (B-CLL) but not in T-CLL or peripheral blood T cells. Two principal effector proteins for cAMP are protein kinase A (PKA) and EPAC, a Rap GDP exchange factor. We here examine whether varying expression of EPAC accounts for the discrepant sensitivity of B-CLL and T cells to PDE4 inhibitor-induced apoptosis. B-CLL and peripheral blood B cells express EPAC1 transcript, while T-CLL, peripheral blood T cells, monocytes and neutrophils do not. Treatment with the PDE4 inhibitor rolipram induces Rap1 activation in B-CLL cells, but not in peripheral blood B cells, T-CLL or any of the normal hematopoietic lineages examined. The EPAC-specific cAMP analogue 8CPT-2Me-cAMP activates Rap1 in B-CLL cells, but, unlike rolipram/forskolin or 8-Br-cAMP, does not induce PKA activation, as judged by phosphorylation of the transcription factor CREB. Unexpectedly, while rolipram/forskolin and 8-Br-cAMP induce apoptosis in B-CLL cells, 8CPT-2Me-cAMP decreased basal apoptosis in CLL cells by an average of 25% (p<.002). Our results demonstrate that B-CLL cells uniquely activate Rap1 in response to PDE4 inhibitors and suggest that physiologic stimuli that activate EPAC may transmit an anti-apoptotic signal. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. El Zein, B. Badran, and E. Sariban VIP differentially activates {beta}2 integrins, CR1, and matrix metalloproteinase-9 in human monocytes through cAMP/PKA, EPAC, and PI-3K signaling pathways via VIP receptor type 1 and FPRL1 J. Leukoc. Biol., April 1, 2008; 83(4): 972 - 981. 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