Induction of cell proliferation/differentiation (P/D) transition requires cell cycle arrest. P/D transition may result from a dual-function of cell cycle regulators that coordinate cell cycle arrest and differentiation activation. Cyclin-dependent kinase (CDK)-activating kinase (CAK) cross-regulates cell cycle and differentiation, while CAK activity is determined by its assembly factor and targeting subunit MAT1 (menage a trois 1). To date, how differentiation is induced from cancer cell proliferation remains unclear. The discovery that retinoic acid (RA) induces myeloid cell differentiation via retinoic acid receptor alpha (RARalpha) introduces a new era of study in cancer cell P/D transition. Our recent studies demonstrate that RA-induced P/D transition in human leukemic HL60 and neuroblastoma CHP126 cells is accompanied by both ubiquitination-proteolysis of MAT1 and decreased CAK phosphorylation of differentiation regulators including retinoblastoma tumor suppressor protein (pRb), RARalpha, and retinoid X receptor alpha (RXRalpha). Manipulating MAT1 abundance shows that MAT1 reduction mimics RA-induced P/D transition, while MAT1 overexpression resists this RA-action. Therefore, we hypothesize that RA-induced ubiquitination-proteolysis of MAT1 may decrease CAK phosphorylation of those differentiation regulators to induce cancer cell P/D transition. Our long-term goal is to understand the role of MAT1 ubiquitination in the switch from cancer cell proliferation to differentiation, which should aid the development of novel approaches to cancer therapy. To test our hypothesis, the experiments are proposed to: a) determine that MAT1 is a substrate for ubiquitination; b) investigate which form of MAT1 is ubiquitinated in vivo; and c) test whether ubiquitination of MAT1 decreases CAK activity to induce P/D transition.
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