Transcriptional coactivator Cited2 induces Bmi1 and Mel18 and controls fibroblast proliferation via Ink4a/ARF

Kamil R Kranc, Simon D Bamforth, José Bragança, Chris Norbury, Maarten van Lohuizen, Shoumo Bhattacharya

Research output: Contribution to journalArticlepeer-review

Abstract

Cited2 (CBP/p300 interacting transactivator with ED-rich tail 2) is required for embryonic development, coactivation of transcription factor AP-2, and inhibition of hypoxia-inducible factor 1 transactivation. Cited2 is induced by multiple growth factors and cytokines and oncogenically transforms cells. Here, we show that the proliferation of Cited2(-/-) mouse embryonic fibroblasts ceases prematurely. This is associated with a reduction in growth fraction, senescent cellular morphology, and increased expression of the cell proliferation inhibitors p16(INK4a), p19(ARF), and p15(INK4b). Deletion of INK4a/ARF (encoding p16(INK4a) and p19(ARF)) completely rescued the defective proliferation of Cited2(-/-) fibroblasts. However, the deletion of INK4a/ARF did not rescue the embryonic malformations observed in Cited2(-/-) mice, indicating that INK4a/ARF-independent pathways are likely to be involved here. We found that Cited2(-/-) fibroblasts had reduced expression of the polycomb-group genes Bmi1 and Mel18, which function as INK4a/ARF and Hox repressors. Complementation with CITED2-expressing retrovirus enhanced proliferation, induced Bmi1/Mel18 expression, and decreased INK4a/ARF expression. Bmi1- and Mel18-expressing retroviruses enhanced the proliferation of Cited2(-/-) fibroblasts, indicating that they function downstream of Cited2. Our results provide genetic evidence that Cited2 controls the expression of INK4a/ARF and fibroblast proliferation, at least in part via the polycomb-group genes Bmi1 and Mel18.
Original languageEnglish
Pages (from-to)7658-66
Number of pages9
JournalMolecular and Cellular Biology
Volume23
Issue number21
DOIs
Publication statusPublished - Nov 2003

Keywords

  • Animals
  • Cell Division
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • Embryo, Mammalian
  • Fibroblasts
  • Gene Expression Regulation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morphogenesis
  • Nuclear Proteins
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Trans-Activators
  • Tumor Suppressor Protein p14ARF

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