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ARF Directly Binds DP1: Interaction with DP1 Coincides with the G₁ Arrest Function of ARF

Abhishek Datta,¹ Jayita Sen,¹ Jussara Hagen,² Chandrashekhar K. Korgaonkar,^2, Michael Caffrey,¹ Dawn E. Quelle,² Douglas E. Hughes,¹ Timothy J. Ackerson,¹ Robert H. Costa,¹ and Pradip Raychaudhuri^1*

Department of Biochemistry and Molecular Genetics, 2302 MBRB (M/C 669), University of Illinois at Chicago, 900 S. Ashland Ave., Chicago, Illinois 60607,¹ Department of Pharmacology, Molecular Biology Graduate Program, University of Iowa College of Medicine, Iowa City, Iowa 52242²

Received 26 November 2004/ Returned for modification 25 February 2005/ Accepted 25 June 2005

The tumor suppressor ARF inhibits cell growth in response to oncogenic stress in a p53-dependent manner. Also, there is an increasing appreciation of ARF's ability to inhibit cell growth via multiple p53-independent mechanisms, including its ability to regulate the E2F pathway. We have investigated the interaction between the tumor suppressor ARF and DP1, the DNA binding partner of the E2F family of factors (E2Fs). We show that ARF directly binds to DP1. Interestingly, binding of ARF to DP1 results in an inhibition of the interaction between DP1 and E2F1. Moreover, ARF regulates the association of DP1 with its target gene, as evidenced by a chromatin immunoprecipitation assay with the dhfr promoter. By analyzing a series of ARF mutants, we demonstrate a strong correlation between ARF's ability to regulate DP1 and its ability to cause cell cycle arrest. S-phase inhibition by ARF is preceded by an inhibition of the E2F-activated genes. Moreover, we provide evidence that ARF inhibits the E2F-activated genes independently of p53 and Mdm2. Also, the interaction between ARF and DP1 is enhanced during oncogenic stress and "culture shock." Taken together, our results show that DP1 is a critical direct target of ARF.

Present address: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Ind.

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