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Merck
  • Activation of both protein kinase A (PKA) type I and PKA type II isozymes is required for retinoid-induced maturation of acute promyelocytic leukemia cells.

Activation of both protein kinase A (PKA) type I and PKA type II isozymes is required for retinoid-induced maturation of acute promyelocytic leukemia cells.

Molecular pharmacology (2013-03-05)
Eric Nguyen, Gro Gausdal, Jacqueline Varennes, Frédéric Pendino, Michel Lanotte, Stein Ove Døskeland, Evelyne Ségal-Bendirdjian
摘要

Acute promyelocytic leukemia (APL) is characterized by granulopoietic differentiation arrest at the promyelocytic stage. In most cases, this defect can be overcome by treatment with all-trans-retinoic acid (ATRA), leading to complete clinical remission. Cyclic AMP signaling has a key role in retinoid treatment efficacy: it enhances ATRA-induced maturation in ATRA-sensitive APL cells (including NB4 cells) and restores it in some ATRA-resistant cells (including NB4-LR1 cells). We show that the two cell types express identical levels of the Cα catalytic subunit and comparable global cAMP-dependent protein kinase A (PKA) enzyme activity. However, the maturation-resistant NB4-LR1 cells have a PKA isozyme switch: compared with the NB4 cells, they have decreased content of the juxtanuclearly located PKA regulatory subunit IIα and PKA regulatory subunit IIβ, and a compensatory increase of the generally cytoplasmically distributed PKA-RIα. Furthermore, the PKA regulatory subunit II exists mainly in the less cAMP-responsive nonautophosphorylated state in the NB4-LR1 cells. By the use of isozyme-specific cAMP analog pairs, we show that both PKA-I and PKA-II must be activated to achieve maturation in NB4-LR1 as well as NB4 cells. Therefore, special attention should be paid to activating not only PKA-I but also PKA-II in attempts to enhance ATRA-induced APL maturation in a clinical setting.

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抗肌动蛋白抗体 兔抗, affinity isolated antibody, buffered aqueous solution