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MAT1-Modulated Cyclin-Dependent Kinase-Activating Kinase Activity Cross-Regulates Neuroblastoma Cell G₁ Arrest and Neurite Outgrowth

¹ Department of Pathology, University of Southern California Keck School of Medicine, and ² Childrens Hospital Los Angeles Research Institute, Los Angeles, California

Cyclin-dependent kinase-activating kinase (CAK) regulates cell cycle G₁ exit, where cells commonly commit either to proliferate or to differentiate. CAK activity in G₁ regulation is determined by its assembly factor and targeting subunit, ménage à trois 1 (MAT1). The precise mechanism of how proliferation/differentiation transition is induced from cancer cell G₁ arrest remains unknown. We present evidence that in neuroblastoma CHP126 cells, CAK interacts with and phosphorylates retinoblastoma tumor suppressor protein (pRb) and retinoid X receptor (RXR). Retinoic acid (RA)-induced neuroblastoma cell proliferation/differentiation transition is associated with decreased CAK activity, as evidenced by a switch from CAK hyperphosphorylation of pRb and RXR to hypophosphorylation of pRb and RXR. Manipulation of MAT1 abundance shows that MAT1 reduction mimics RA-induced hypophosphorylation of pRb/RXR, proliferation inhibition, and neurite outgrowth, whereas MAT1 overexpression resists these RA actions. Thus, these findings reveal an important mechanism by which MAT1-modulated CAK activity is crucial in the switch from proliferation to differentiation in neuroblastoma cells.

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