| Abstract: |
Germline RB1 mutations strongly predispose humans to cone precursor–derived retinoblastomas and strongly predispose mice to pituitary tumors, yet shared cell type–specific circuitry that sensitizes these different cell types to the loss of RB1 has not been defined. Here we show that the cell type–restricted thyroid hormone receptor isoform TRb2 sensitizes to RB1 loss in both settings by antagonizing the widely expressed and tumor-suppressive TRb1. TRb2 promoted expression of the E3 ubiquitin ligase SKP2, a critical factor for RB1-mutant tumors, by enabling EMI1/FBXO5–dependent inhibition of SKP2 degradation. In RB1 wild-type neuroblastoma cells, endogenous Rb or ectopic TRb2 was required to sustain SKP2 expression as well as cell viability and proliferation. These results suggest that in certain contexts, Rb loss enables TRb1-dependent suppression of SKP2 as a safeguard against RB1-deficient tumorigenesis. TRb2 counteracts TRb1, thus disrupting this safeguard and promoting development of RB1-deficient malignancies. © 2017 American Association for Cancer Research. |
