Abstract
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 β2 (TRβ2), 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 TRβ1. However, it is unclear how TRβ2 opposes TRβ1 to enable SKP2 expression and cell proliferation. Here, we show that in human retinoblastoma cells TRβ2 mRNA encodes two TRβ2 protein isoforms: a predominantly cytoplasmic 54-kDa protein (TRβ2-54) corresponding to the well-characterized full-length murine Trβ2 and an N-terminally truncated and exclusively cytoplasmic 46-kDa protein (TRβ2-46) that starts at Met-79. Whereas TRβ2 knockdown decreased SKP2 expression and impaired retinoblastoma cell cycle progression, re-expression of TRβ2-46 but not TRβ2-54 stabilized SKP2 and restored proliferation to an extent similar to that of ectopic SKP2 restoration. We conclude that TRβ2-46 is an oncogenic thyroid hormone receptor isoform that promotes SKP2 expression and SKP2-dependent retinoblastoma cell proliferation.
Highlights
Retinoblastoma is a childhood retinal tumor that develops from cone photoreceptor precursors in response to inactivating RB1 mutations and loss of functional RB protein
Because retinoblastomas are derived from cone precursors [2, 3] and thyroid hormone receptor 2 (TR2) is solely detected in cone precursors in the developing human retina [4, 24], we examined whether TR2-54 and TR2-46 are expressed in the cone precursor cell of origin
We report that retinoblastoma cells express two functionally distinct TR2 isoforms, here designated TR2-46 and TR2-54 according to their predicted molecular masses
Summary
Cancers are caused by abnormalities in oncogenes or tumorsuppressor genes that initiate and advance tumorigenesis. Human cone precursor circuitry may sensitize to RB1 mutation via intrinsic high expression of oncoproteins, such as MYCN and MDM2, and cone lineage transcription factors, such as retinoid X receptor-␥ (RXR␥) and thyroid hormone receptor 2 (TR2) [2, 4]. TR2 is highly expressed in a limited number of cell types, including cone photoreceptor precursors, pituicytes, and cochlear hair cells [7,8,9], each of which aberrantly proliferates in response to RB loss [2, 10, 11]. TR2 and TR1 are produced from the same THRB gene but use alternative transcriptional promoters and N-terminal coding exons [8, 14] They both have canonical nuclear hormone receptor structure with an N-terminal “A/B” corepressor and coactivator–
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