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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4407-4416.
Prepublished online as a Blood First Edition Paper on January 19, 2006; DOI 10.1182/blood-2005-08-3263.


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Submitted August 12, 2005
Accepted December 28, 2005

Global transcriptional coactivators CREB-binding protein and p300 are highly essential collectively but not individually in peripheral B-cells

Wu Xu, Tomofusa Fukuyama, Paul A Ney, Demin Wang, Jerold Rehg, Kelli Boyd, Jan M van Deursen, and Paul K Brindle*

Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, USA
Blood Research Institute, BloodCenter of Wisconsis, Milwaukee, WI, USA; Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Department of Pediatric and Adolescent Medicine and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA

* Corresponding author; email: paul.brindle{at}stjude.org.

CREB-binding protein (CBP) and its paralog p300 are transcriptional coactivators that physically or functionally interact with over 320 mammalian and viral proteins, including 36 that are essential for B-cells in mice. CBP and p300 are generally considered limiting for transcription, yet their roles in adult cell lineages are largely unknown since homozygous null mutations in either gene, or compound heterozygosity, cause early embryonic lethality in mice. We tested the hypotheses that CBP and p300 are limiting and that each has unique properties in B-cells, by using mice with Cre/LoxP conditional knockout alleles for CBP (CBPflox) and p300 (p300flox), and which carry CD19Cre that initiates floxed gene recombination at the pro-B-cell stage. CD19Cre mediated loss of CBP or p300 led to surprisingly modest deficits in B-cell numbers, whereas inactivation of both genes was not tolerated by peripheral B-cells. There was a moderate decrease in B-cell receptor (BCR)-responsive gene expression in CBP or p300 homozygous null B-cells, suggesting that CBP and p300 are essential for this signaling pathway that is crucial for B-cell homeostasis. These results indicate that individually CBP and p300 are partially limiting beyond the pro-B-cell stage, and that other coactivators in B-cells cannot replace their combined loss.


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