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Lookup NU author(s): Dr Simon BamforthORCiD
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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.
Author(s): Bamforth SD; Kranc KR; Braganca J; Norbury C; van Lohuizen M; Bhattacharya S
Publication type: Article
Publication status: Published
Journal: Molecular and Cellular Biology
Year: 2003
Volume: 23
Issue: 21
Pages: 7658-7666
ISSN (print): 1541-7786
ISSN (electronic): 1557-3125
Publisher: American Association for Cancer Research
URL: http://dx.doi.org/10.1128/MCB.23.21.7658-7666.2003
DOI: 10.1128/MCB.23.21.7658-7666.2003
Notes: 0270-7306 (Print) Journal Article
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