[HTML][HTML] MicroRNA-181a-mediated downregulation of AC9 protein decreases intracellular cAMP level and inhibits ATRA-induced APL cell differentiation

LK Zhuang, GP Xu, XR Pan, YJ Lou, QP Zou… - Cell Death & …, 2014 - nature.com
LK Zhuang, GP Xu, XR Pan, YJ Lou, QP Zou, D Xia, WW Yan, YT Zhang, PM Jia, JH Tong
Cell Death & Disease, 2014nature.com
AC9 is one of the adenylate cyclase (AC) isoforms, which catalyze the conversion of ATP to
cAMP, an important second messenger. We previously found that the integration of
cAMP/PKA pathway with nuclear receptor-mediated signaling was required during all-trans
retinoic acid (ATRA)-induced maturation of acute promyelocytic leukemia (APL) cells. Here
we showed that AC9 could affect intracellular cAMP level and enhance the trans-activity of
retinoic acid receptor. Knockdown of AC9 in APL cell line NB4 could obviously inhibit ATRA …
Abstract
AC9 is one of the adenylate cyclase (AC) isoforms, which catalyze the conversion of ATP to cAMP, an important second messenger. We previously found that the integration of cAMP/PKA pathway with nuclear receptor-mediated signaling was required during all-trans retinoic acid (ATRA)-induced maturation of acute promyelocytic leukemia (APL) cells. Here we showed that AC9 could affect intracellular cAMP level and enhance the trans-activity of retinoic acid receptor. Knockdown of AC9 in APL cell line NB4 could obviously inhibit ATRA-induced differentiation. We also demonstrated that miR-181a could decrease AC9 expression by targeting 3′ UTR of AC9 mRNA, finally controlling the production of intracellular cAMP. The expression of miR-181a itself could be inhibited by CEBPα, probably accounting for the differential expression of miR-181a in NB4 and ATRA-resistant NB4-R1 cells. Moreover, we found that AC9 expression was relatively lower in newly diagnosed or relapsed APL patients than in both complete remission and non-leukemia cases, closely correlating with the leukemogenesis of APL. Taken together, our studies revealed for the first time the importance of miR-181a-mediated AC9 downregulation in APL. We also suggested the potential value of AC9 as a biomarker in the clinical diagnosis and treatment of leukemia.
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