Rb suppresses human cone precursor-derived retinoblastoma tumors
| Autor: | David Cobrinik, Lu Wang, Suresh C. Jhanwar, Xiaoliang L. Xu, Hardeep Singh, Donglai Qi, Bradford K. Poulos, David H. Abramson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cell type
Retinoblastoma-Like Protein p107 medicine.disease_cause N-Myc Proto-Oncogene Protein Retinal Cone Photoreceptor Cells Retinoblastoma Protein Article 03 medical and health sciences 0302 clinical medicine medicine Humans Genes Retinoblastoma Nuclear protein S-Phase Kinase-Associated Proteins 030304 developmental biology Oncogene Proteins 0303 health sciences Multidisciplinary Retinoblastoma-Like Protein p130 biology Retinoblastoma Stem Cells Retinoblastoma protein Nuclear Proteins Proto-Oncogene Proteins c-mdm2 medicine.disease eye diseases E2F Transcription Factors Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Organ Specificity 030220 oncology & carcinogenesis Cancer research biology.protein Heterografts Mdm2 Carcinogenesis |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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