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

Abstract

Cyclin-dependent kinase-activating kinase (CAK) regulates cell cycle G 1 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 α (RXRα). 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 RXRα to hypophosphorylation of pRb and RXRα. Manipulation of MAT1 abundance shows that MAT1 reduction mimics RA-induced hypophosphorylation of pRb/RXRα, 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.