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- Title
Rb suppresses human cone-precursor-derived retinoblastoma tumours.
- Authors
Xu, Xiaoliang L.; Singh, Hardeep P.; Qi, Dong-Lai; Wang, Lu; Poulos, Bradford K.; Abramson, David H.; Jhanwar, Suresh C.; Cobrinik, David
- Abstract
Retinoblastoma is a childhood retinal tumour that initiates in response to biallelic RB1 inactivation and loss of functional retinoblastoma (Rb) protein. Although Rb has diverse tumour-suppressor functions and is inactivated in many cancers, germline RB1 mutations predispose to retinoblastoma far more strongly than to other malignancies. This tropism suggests that retinal cell-type-specific circuitry sensitizes to Rb loss, yet the nature of the circuitry and the cell type in which it operates have been unclear. Here we show that post-mitotic human cone precursors are uniquely sensitive to Rb depletion. Rb knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN and MDM2. Proliferation of Rb-depleted cones and retinoblastoma cells also depended on the Rb-related protein p107, SKP2, and a p27 downregulation associated with cone precursor maturation. Moreover, Rb-depleted cone precursors formed tumours in orthotopic xenografts with histological features and protein expression typical of human retinoblastoma. These findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma. More generally, they demonstrate that cell-type-specific circuitry can collaborate with an initiating oncogenic mutation to enable tumorigenesis.
- Subjects
RETINOBLASTOMA; CANCER; RETINA; CANCER cell proliferation; NEOPLASTIC cell transformation
- Publication
Nature, 2014, Vol 514, Issue 7522, p385
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature13813