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Molecular and Cellular Biology, May 2008, p. 3127-3138, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02089-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

p110 CUX1 Cooperates with E2F Transcription Factors in the Transcriptional Activation of Cell Cycle-Regulated Genes{triangledown} ,{dagger}

Mary Truscott,1,2 Ryoko Harada,1 Charles Vadnais,1,2 François Robert,3 and Alain Nepveu1,2,4,5*

Molecular Oncology Group, McGill University Health Center,1 Departments of Biochemistry,2 Medicine,4 Oncology, McGill University, Montreal, Canada,5 Institut de Recherches Cliniques de Montréal, Montreal, Canada3

Received 21 November 2007/ Returned for modification 3 January 2008/ Accepted 6 March 2008

The transcription factor p110 CUX1 was shown to stimulate cell proliferation by accelerating entry into S phase. As p110 CUX1 can function as a transcriptional repressor or activator depending on promoter context, we investigated its mechanism of transcriptional activation using the DNA polymerase {alpha} gene promoter as a model system. Linker-scanning analysis revealed that a low-affinity E2F binding site is required for transcriptional activation. Moreover, coexpression with a dominant-negative mutant of DP-1 suggested that endogenous E2F factors are indeed needed for p110-mediated activation. Tandem affinity purification, coimmunoprecipitation, chromatin immunoprecipitation, and reporter assays indicated that p110 CUX1 can engage in weak protein-protein interactions with E2F1 and E2F2, stimulate their recruitment to the DNA polymerase {alpha} gene promoter, and cooperate with these factors in transcriptional activation. On the other hand, in vitro assays suggested that the interaction between CUX1 and E2F1 either is not direct or is regulated by posttranslational modifications. Genome-wide location analysis revealed that targets common to p110 CUX1 and E2F1 included many genes involved in cell cycle, DNA replication, and DNA repair. Comparison of the degree of enrichment for various E2F factors suggested that binding of p110 CUX1 to a promoter will favor the specific recruitment of E2F1, and to a lesser extent E2F2, over E2F3 and E2F4. Reporter assays on a subset of common targets confirmed that p110 CUX1 and E2F1 cooperate in their transcriptional activation. Overall, our results show that p110 CUX1 and E2F1 cooperate in the regulation of many cell cycle genes.

* Corresponding author. Mailing address: McGill University, Molecular Oncology Group, 687 Pine Ave. West, Rm. H5.21, Montreal H3A-1A1, Canada. Phone: (514) 934-1934, ext. 35842. Fax: (514) 843-1478. E-mail: alain.nepveu{at}mcgill.ca

{triangledown} Published ahead of print on 17 March 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2008, p. 3127-3138, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02089-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kedinger, V., Sansregret, L., Harada, R., Vadnais, C., Cadieux, C., Fathers, K., Park, M., Nepveu, A. (2009). p110 CUX1 Homeodomain Protein Stimulates Cell Migration and Invasion in Part through a Regulatory Cascade Culminating in the Repression of E-cadherin and Occludin. J. Biol. Chem. 284: 27701-27711 [Abstract] [Full Text]  
  • Rabinovich, A., Jin, V. X., Rabinovich, R., Xu, X., Farnham, P. J. (2008). E2F in vivo binding specificity: Comparison of consensus versus nonconsensus binding sites. Genome Res 18: 1763-1777 [Abstract] [Full Text]  


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