Xu Xiaoliang L, Li Zhengke, Liu Aihong, Fan Xianqun, Hu Dan-Ning, Qi Dong-Lai, Chitty David W, Jia Renbing, Qui Jianping, Wang Justin Q, Sharaf Jake, Zou Jun, Weiss Rebecca, Huang Hongyan, Joseph Walter J, Ng Lily, Rosen Richard, Shen Binghui, Reid Mark W, Forrest Douglas, Abramson David H, Singer Samuel, Cobrinik David, Jhanwar Suresh C
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
Cancer Res. 2017 Dec 15;77(24):6838-6850. doi: 10.1158/0008-5472.CAN-16-3299. Epub 2017 Sep 28.
Germline 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 has not been defined. Here we show that the cell type-restricted thyroid hormone receptor isoform TRβ2 sensitizes to 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 -mutant tumors, by enabling EMI1/FBXO5-dependent inhibition of SKP2 degradation. In 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 -deficient tumorigenesis. TRβ2 counteracts TRβ1, thus disrupting this safeguard and promoting development of -deficient malignancies. .
种系突变使人类极易患视锥前体细胞来源的视网膜母细胞瘤，并使小鼠极易患垂体瘤，但尚未明确使这些不同细胞类型对 缺失敏感的共同细胞类型特异性信号通路。在这里，我们表明，细胞类型受限的甲状腺激素受体亚型TRβ2通过拮抗广泛表达的肿瘤抑制因子TRβ1，在这两种情况下均对 缺失敏感。TRβ2通过实现EMI1/FBXO5依赖性抑制SKP2降解，促进E3泛素连接酶SKP2的表达，SKP2是 -突变肿瘤的关键因子。在野生型神经母细胞瘤细胞中，内源性Rb或异位TRβ2是维持SKP2表达以及细胞活力和增殖所必需的。这些结果表明，在某些情况下，Rb缺失使TRβ1依赖性抑制SKP2，作为防止 -缺陷肿瘤发生的一种保护机制。TRβ2抵消TRβ1，从而破坏这种保护机制并促进 -缺陷恶性肿瘤的发展。
