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Rapid induction of cAMP/PKA pathway during retinoic acid-induced acute promyelocytic leukemia cell differentiation

Leukemia volumeĀ 18,Ā pages 285ā€“292 (2004)Cite this article

Abstract

The second messenger cyclic adenosine monophosphate (cAMP) plays an important role in cell proliferation, differentiation and apoptosis. In the present work, we evaluated the cAMP signaling in acute promyelocytic leukemia (APL) cells in the context of differentiation induced by all-trans retinoic acid (ATRA). There was a marked increase in the intracellular cAMP level within a few minutes after treatment with ATRA in APL cell line NB4 and fresh APL cells, whereas no such phenomenon was observed in NB4-R1 cells that are resistant to ATRA-induced maturation. In addition, the basal level of intracellular cAMP was lower in NB4-R1 than in NB4 cells. Mechanistic study showed that this induction of cAMP was mediated through the activation of adenylate cyclase. Moreover, we found that cAMP-dependent protein kinase (PKA) activity was quickly upregulated in parallel in ATRA-treated NB4 cells, and the phosphorylation of RARĪ± by PKA could increase its transactivation effect. Use of H-89, an inhibitor of PKA, could partially suppress the transcriptional expression of ATRA target genes and ATRA-induced differentiation of APL cells. Taken together, we suggested a crosstalk between ATRA-induced cytosolic pathway and nuclear pathway in APL cell differentiation.

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Acknowledgements

This work was supported in part by Chinese National Key Basic Research Project 973(2002CB512805), National Natural Science Foundation of China (30271466), Chinese National High Tech Program (863), Shanghai Municipal Commission for Science and Technology, Shanghai Municipal Commission for Education, Shanghai ā€˜Shu Guangā€™ Research Project, l'Association Franco-Chinoise pour la Recherche Scientifique et Technique (PRA), Samuel Waxman Cancer Research Foundation and Clyde Wu Foundation of SIH. We thank all members of the SIH and SKLHGR for their support.

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  1. Q Zhao and J Tao: These authors contributed equally to this work

Authors and Affiliations

  1. State Key Lab for Human Genome Research (SKLHGR), Shanghai Institute of Hematology, Ruijin Hospital, Samuel Waxman Cancer Research Foundation Laboratory of Shanghai Second Medical University (SSMU), Shanghai, China

    Q Zhao,Ā J Tao,Ā Q Zhu,Ā P-M Jia,Ā A-X Dou,Ā F Cheng,Ā G-Q Chen,Ā S-J Chen,Ā Z ChenĀ &Ā J-H Tong

  2. Health Science Center, Shanghai Second Medical University and the Shanghai Institute of Biological Science, Chinese Academy of Sciences, China

    Q Zhao,Ā X LiĀ &Ā G-Q Chen

  3. Department of Medicine, Division of Neoplastic Diseases, The Mount Sinai Medical Center, New York, NY, USA

    S Waxman

  4. INSERM U496, Centre G Hayem, Hopital Saint Louis, Paris, France

    M Lanotte

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Correspondence to J-H Tong.

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Zhao, Q., Tao, J., Zhu, Q. et al. Rapid induction of cAMP/PKA pathway during retinoic acid-induced acute promyelocytic leukemia cell differentiation. Leukemia 18, 285ā€“292 (2004). https://doi.org/10.1038/sj.leu.2403226

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