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Molecular and Cellular Biology, November 2003, p. 7658-7666, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7658-7666.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Transcriptional Coactivator Cited2 Induces Bmi1 and Mel18 and Controls Fibroblast Proliferation via Ink4a/ARF

Kamil R. Kranc,1,2 Simon D. Bamforth,1 José Bragança,1 Chris Norbury,3 Maarten van Lohuizen,4 and Shoumo Bhattacharya1*

Departments of Cardiovascular Medicine,1 Biochemistry, Wellcome Trust Centre for Human Genetics,2 Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom,3 Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands4

Received 10 April 2003/ Returned for modification 19 May 2003/ Accepted 14 July 2003

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 p16INK4a, p19ARF, and p15INK4b. Deletion of INK4a/ARF (encoding p16INK4a and p19ARF) 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.

* Corresponding author. Mailing address: Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, United Kingdom. Phone: 44-1865-287581. Fax: 44-1865-287661. E-mail: sbhattac{at}well.ox.ac.uk.

Molecular and Cellular Biology, November 2003, p. 7658-7666, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7658-7666.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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