A novel thyroid hormone receptor isoform, TR{beta}2-46, promotes SKP2 expression and retinoblastoma cell proliferation [Cell Biology] (Journal of Biological Chemistry)

Retinoblastoma is a childhood retinal tumor that develops from cone photoreceptor precursors in response to inactivating RB1 mutations and loss of functional RB protein. The cone precursor`s response to RB loss involves cell type-specific signaling circuitry that helps to drive tumorigenesis. One component of the cone precursor circuitry, the thyroid hormone receptor ?2 (TR?2), enables the aberrant proliferation of diverse RB-deficient cells in part by opposing the down-regulation of S-phase kinase-associated protein 2 (SKP2) by the more widely expressed and tumor-suppressive TR?1. However, it is unclear how TR?2 opposes TR?1 to enable SKP2 expression and cell proliferation. Here, we show that in human retinoblastoma cells TR?2 mRNA encodes two TR?2 protein isoforms: a predominantly cytoplasmic 54-kDa protein (TR?2-54) corresponding to the well-characterized full-length murine Tr?2 and an N-terminally truncated and exclusively cytoplasmic 46-kDa protein (TR?2-46) that starts at Met-79. Whereas TR?2 knockdown decreased SKP2 expression and impaired retinoblastoma cell cycle progression, re-expression of TR?2-46 but not TR?2-54 stabilized SKP2 and restored proliferation to an extent similar to that of ectopic SKP2 restoration. We conclude that TR?2-46 is an oncogenic thyroid hormone receptor isoform that promotes SKP2 expression and SKP2-dependent retinoblastoma cell proliferation.