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

Mol Cell Biol. 2003 Nov;23(21):7658-66. doi: 10.1128/MCB.23.21.7658-7666.2003.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Bmi1 protein, mouse
  • CITED2 protein, human
  • Cdkn2a protein, mouse
  • Cited2 protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • Nuclear Proteins
  • PCGF2 protein, human
  • Pcgf6 protein, mouse
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Trans-Activators
  • Tumor Suppressor Protein p14ARF
  • Polycomb Repressive Complex 1