Rapid induction of cAMP/PKA pathway during retinoic acid-induced acute promyelocytic leukemia cell differentiation.
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 RARalpha 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.
Zhao
Q
Q
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.
Tao
J
J
Zhu
Q
Q
Jia
P-M
PM
Dou
A-X
AX
Li
X
X
Cheng
F
F
Waxman
S
S
Chen
G-Q
GQ
Chen
S-J
SJ
Lanotte
M
M
Chen
Z
Z
Tong
J-H
JH
D000262:Adenylyl Cyclases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D020239:Receptor Cross-Talk; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015290:Second Messenger Systems / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
C000607071:RARA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases