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Molecular and Cellular Biology, May 2009, p. 2673-2693, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01140-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Regulation of p53 by TopBP1: a Potential Mechanism for p53 Inactivation in Cancer{triangledown} ,{dagger}

Kang Liu,1 Naresh Bellam,1 Hui-Yi Lin,2,{ddagger} Bing Wang,1 Cecil R. Stockard,3 William E. Grizzle,3 and Weei-Chin Lin1,4*

Division of Hematology and Oncology, Department of Medicine,1 Medical Statistics Section, Department of Medicine,2 Department of Pathology,3 Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-33004

Received 18 July 2008/ Returned for modification 29 August 2008/ Accepted 3 March 2009

Proper control of the G1/S checkpoint is essential for normal proliferation. The activity of p53 must be kept at a very low level under unstressed conditions to allow growth. Here we provide evidence supporting a crucial role for TopBP1 in actively repressing p53. Depletion of TopBP1 upregulates p53 target genes involved in cell cycle arrest and apoptosis and enhances DNA damage-induced apoptosis. The regulation is mediated by an interaction between the seventh and eighth BRCT domains of TopBP1 and the DNA-binding domain of p53, leading to inhibition of p53 promoter binding activity. Importantly, TopBP1 overexpression is found in 46 of 79 primary breast cancer tissues and is associated with high tumor grade and shorter patient survival time. Overexpression of TopBP1 to a level comparable to that seen in breast tumors leads to inhibition of p53 target gene expression and DNA damage-induced apoptosis and G1 arrest. Thus, a physiological level of TopBP1 is essential for normal G1/S transition, but a pathological level of TopBP1 in cancer may perturb p53 function and contribute to an aggressive tumor behavior.

* Corresponding author. Mailing address: Shelby 815, 1530 3rd Ave. S, Birmingham, AL 35294-3300. Phone: (205) 934-3979. Fax: (205) 975-6911. E-mail: wclin{at}uab.edu

{triangledown} Published ahead of print on 16 March 2009.

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

{ddagger} Present address: Department of Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL 33612.

Molecular and Cellular Biology, May 2009, p. 2673-2693, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01140-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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