Rb suppresses human cone-precursor-derived retinoblastoma tumours Journal Article
| Authors: | Xu, X. L.; Singh, H. P.; Wang, L.; Qi, D. L.; Poulos, B. K.; Abramson, D. H.; Jhanwar, S. C.; Cobrinik, D. |
| Article Title: | Rb suppresses human cone-precursor-derived retinoblastoma tumours |
| Abstract: | Retinoblastomais 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, germlineRB1mutations 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 beenunclear. 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 ap27down regulation associated with cone precursormaturation. 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 celltype- specific circuitry can collaborate with an initiating oncogenic mutation to enable tumorigenesis. |
| Keywords: | controlled study; human tissue; protein expression; unclassified drug; oncoprotein; genetics; mutation; histopathology; nonhuman; cell proliferation; mouse; metabolism; gene; gene expression; nuclear protein; protein depletion; animal experiment; animal model; protein; retinoblastoma; pathology; histology; carcinogenesis; stem cell; cell transformation, neoplastic; nuclear proteins; gene expression regulation; tumor suppressor gene; gene expression regulation, neoplastic; xenograft; cell transformation; transcription factor e2f; oncogene proteins; protein p27; organ specificity; stem cells; antibody specificity; down regulation; fetus; gene induction; tumor; retinoblastoma protein; protein p107; protein p130; retinoblastoma-like protein p107; retinoblastoma-like protein p130; protein mycn; s phase kinase associated protein 2; s-phase kinase-associated proteins; protein mdm2; proto-oncogene proteins c-mdm2; mdm2 protein, human; mycn protein, human; retina cone; retinal cone photoreceptor cells; s phase kinase associated protein; e2f transcription factors; genes, retinoblastoma; cancer; humans; human; male; article; rbl1 protein, human; retinoblastoma cell line; heterografts |
| Journal Title: | Nature |
| Volume: | 514 |
| Issue: | 7522 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2014-10-16 |
| Start Page: | 385 |
| End Page: | 388 |
| Language: | English |
| DOI: | 10.1038/nature13813 |
| PUBMED: | 25252974 |
| PROVIDER: | scopus |
| PMCID: | PMC4232224 |
| DOI/URL: | |
| Notes: | Export Date: 1 December 2014 -- Source: Scopus |
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