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Retinoic acid induces leukemia cell G₁ arrest and transition into differentiation by inhibiting cyclin-dependent kinase-activating kinase binding and phosphorylation of PML/RAR

Jian-guang Wang^*, Lora W. Barsky, Elai Davicioni, Kenneth I. Weinberg^,, Timothy J. Triche^*,, Xiao-kun Zhang and Lingtao Wu^*,,1

^* Department of Pathology,

Division of Research Immunology/BMT, Childrens Hospital Los Angeles Saban Research Institute, Los Angeles, California, USA;

The Burnham Institute Cancer Center, La Jolla, California, USA;

University of Southern California Keck School of Medicine, Los Angeles, California, USA

¹Correspondence: Department of Pathology, MS# 103, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, 4650 Sunset Blvd., Los Angeles, CA 90027 USA. E-mail: lingtaow{at}usc.edu

ABSTRACT

Acute promyelocytic leukemia (APL) cells express promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR) fusion protein, which leads to the blocking of APL cell differentiation. Treatment of APL with all-trans-retinoic acid (ATRA) induces disease remission by in vivo differentiation of APL cells. Differentiation requires cell cycle exit; yet how ATRA couples cell cycle exit to differentiation of APL remains largely unknown. We previously found that ATRA-induced cell differentiation accompanies ubiquitination-proteolysis of ménage à trois 1 (MAT1), an assembly factor and targeting subunit of cyclin-dependent kinase (CDK)-activating kinase (CAK) that regulates G₁ exit. We report here that CAK binds to and phosphorylates PML/RAR in actively proliferating APL cells. In response to ATRA, PML/RAR is dissociated from CAK, leading to MAT1 degradation, G₁ arrest, and decreased CAK phosphorylation of PML/RAR. CAK phosphorylation of PML/RAR is inhibited when MAT1 levels are reduced. Both MAT1 degradation and PML/RAR hypophosphorylation occur in ATRA-induced G₁-arresting cells undergoing differentiation but not in the synchronized G₁ cells that do not differentiate. These findings reveal a novel ATRA signaling on APL cell differentiation, in which ATRA coordinates G₁ arrest and transition into differentiation by inducing MAT1 degradation and PML/RAR hypophosphorylation through disrupting PML/RAR binding and phosphorylation by CAK.—Wang, J.-g., Barsky, L. W., Davicioni, E., Weinberg, K. I., Triche, T. J., Zhang, X.-k., and Wu, L. Retinoic acid induces leukemia cell G₁ arrest and transition into differentiation by inhibiting cyclin-dependent kinase-activating kinase binding and phosphorylation of PML/RAR.

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