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J Biol Chem, Vol. 274, Issue 31, 22013-22018, July 30, 1999

Retinoic Acid Promotes Ubiquitination and Proteolysis of Cyclin D1 during Induced Tumor Cell Differentiation

Michael J. Spinella^§, Sarah J. Freemantle, David Sekula, Jeffrey H. Chang, Allison J. Christie, and Ethan Dmitrovsky^§

From the  Department of Pharmacology and Toxicology, Dartmouth Medical School and the  Department of Medicine and the ^§ Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Hanover, New Hampshire 03755

Mechanisms by which differentiation programs engage the cell cycle are poorly understood. This study demonstrates that retinoids promote ubiquitination and degradation of cyclin D1 during retinoid-induced differentiation of human embryonal carcinoma cells. In response to all-trans-retinoic acid (RA) treatment, the human embryonal carcinoma cell line NT2/D1 exhibits a progressive decline in cyclin D1 expression beginning when the cells are committed to differentiate, but before onset of terminal neuronal differentiation. The decrease in cyclin D1 protein is tightly associated with the accumulation of hypophosphorylated forms of the retinoblastoma protein and G₁ arrest. In contrast, retinoic acid receptor -deficient NT2/D1-R1 cells do not growth-arrest or accumulate in G₁ and have persistent cyclin D1 overexpression despite RA treatment. Notably, stable transfection of retinoic acid receptor  restores RA-mediated growth suppression and differentiation to NT2/D1-R1 cells and restores the decline of cyclin D1. The proteasome inhibitor LLnL blocks this RA-mediated decline in cyclin D1. RA treatment markedly accelerates ubiquitination of wild-type cyclin D1, but not a cyclin D1 (T286A) mutant. Transient expression of cyclin D1 (T286A) in NT2/D1 cells blocks RA-mediated transcriptional decline of a differentiation-sensitive reporter plasmid and represses induction of immunophenotypic neuronal markers. Taken together, these findings strongly implicate RA-mediated degradation of cyclin D1 as a means of coupling induced differentiation and cell cycle control of human embryonal carcinoma cells.

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