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SKP2 Activation by Thyroid Hormone Receptor β2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells.

SKP2 Activation by Thyroid Hormone Receptor β2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells.
Author Information (click to view)

Xu XL, Li Z, Liu A, Fan X, Hu DN, Qi DL, Chitty DW, Jia R, Qui J, Wang JQ, Sharaf J, Zou J, Weiss R, Huang H, Joseph WJ, Ng L, Rosen R, Shen B, Reid MW, Forrest D, Abramson DH, Singer S, Cobrinik D, Jhanwar SC,


Xu XL, Li Z, Liu A, Fan X, Hu DN, Qi DL, Chitty DW, Jia R, Qui J, Wang JQ, Sharaf J, Zou J, Weiss R, Huang H, Joseph WJ, Ng L, Rosen R, Shen B, Reid MW, Forrest D, Abramson DH, Singer S, Cobrinik D, Jhanwar SC, (click to view)

Xu XL, Li Z, Liu A, Fan X, Hu DN, Qi DL, Chitty DW, Jia R, Qui J, Wang JQ, Sharaf J, Zou J, Weiss R, Huang H, Joseph WJ, Ng L, Rosen R, Shen B, Reid MW, Forrest D, Abramson DH, Singer S, Cobrinik D, Jhanwar SC,

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Cancer research 2017 09 2877(24) 6838-6850 doi 10.1158/0008-5472.CAN-16-3299

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 TRβ2 sensitizes to RB1 loss in both settings by antagonizing the widely expressed and tumor-suppressive TRβ1. TRβ2 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 TRβ2 was required to sustain SKP2 expression as well as cell viability and proliferation. These results suggest that in certain contexts, Rb loss enables TRβ1-dependent suppression of SKP2 as a safeguard against RB1-deficient tumorigenesis. TRβ2 counteracts TRβ1, thus disrupting this safeguard and promoting development of RB1-deficient malignancies. Cancer Res; 77(24); 6838-50. ©2017 AACR.

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