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Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis.
Blood. 2004 Apr 01; 103(7):2661-7.Blood

Abstract

Type 4 cyclic adenosine monophosphate (cAMP) 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 (exchange protein directly activated by cAMP), a Rap guanosine 5'-diphosphate (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, whereas 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 analog 8CPT-2Me-cAMP (8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cAMP) activates Rap1 in B-CLL cells, but, unlike rolipram/forskolin or 8-Bromo-cAMP, it does not induce PKA activation, as judged by phosphorylation of the transcription factor cAMP-response element binding protein (CREB). Unexpectedly, whereas rolipram/forskolin and 8-Bromo-cAMP induce apoptosis in B-CLL cells, 8CPT-2Me-cAMP decreased basal apoptosis in B-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 antiapoptotic signal.

Authors+Show Affiliations

Department of Medicine, Section of Hematology/Oncology, Boston Medical Center, MA 02118, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14615375

Citation

Tiwari, Sanjay, et al. "Among Circulating Hematopoietic Cells, B-CLL Uniquely Expresses Functional EPAC1, but EPAC1-mediated Rap1 Activation Does Not Account for PDE4 Inhibitor-induced Apoptosis." Blood, vol. 103, no. 7, 2004, pp. 2661-7.
Tiwari S, Felekkis K, Moon EY, et al. Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis. Blood. 2004;103(7):2661-7.
Tiwari, S., Felekkis, K., Moon, E. Y., Flies, A., Sherr, D. H., & Lerner, A. (2004). Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis. Blood, 103(7), 2661-7.
Tiwari S, et al. Among Circulating Hematopoietic Cells, B-CLL Uniquely Expresses Functional EPAC1, but EPAC1-mediated Rap1 Activation Does Not Account for PDE4 Inhibitor-induced Apoptosis. Blood. 2004 Apr 1;103(7):2661-7. PubMed PMID: 14615375.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis. AU - Tiwari,Sanjay, AU - Felekkis,Kyriacos, AU - Moon,Eun-Yi, AU - Flies,Amanda, AU - Sherr,David H, AU - Lerner,Adam, Y1 - 2003/11/13/ PY - 2003/11/15/pubmed PY - 2004/5/12/medline PY - 2003/11/15/entrez SP - 2661 EP - 7 JF - Blood JO - Blood VL - 103 IS - 7 N2 - Type 4 cyclic adenosine monophosphate (cAMP) 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 (exchange protein directly activated by cAMP), a Rap guanosine 5'-diphosphate (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, whereas 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 analog 8CPT-2Me-cAMP (8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cAMP) activates Rap1 in B-CLL cells, but, unlike rolipram/forskolin or 8-Bromo-cAMP, it does not induce PKA activation, as judged by phosphorylation of the transcription factor cAMP-response element binding protein (CREB). Unexpectedly, whereas rolipram/forskolin and 8-Bromo-cAMP induce apoptosis in B-CLL cells, 8CPT-2Me-cAMP decreased basal apoptosis in B-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 antiapoptotic signal. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/14615375/Among_circulating_hematopoietic_cells_B_CLL_uniquely_expresses_functional_EPAC1_but_EPAC1_mediated_Rap1_activation_does_not_account_for_PDE4_inhibitor_induced_apoptosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)43876-5 DB - PRIME DP - Unbound Medicine ER -