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Molecular and Cellular Biology, February 2008, p. 997-1006, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01848-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Degradation of the Tumor Suppressor PML by Pin1 Contributes to the Cancer Phenotype of Breast Cancer MDA-MB-231 Cells{triangledown}

Erin L. Reineke,1 Minh Lam,1,2 Qing Liu,1 Yu Liu,1 Kristopher J. Stanya,1 Kun-Sang Chang,3 Anthony R. Means,4 and Hung-Ying Kao1*

Department of Biochemistry, School of Medicine, Case Western Reserve University,1 Research Institute of University Hospitals of Cleveland and Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland, 10900 Euclid Avenue, Cleveland, Ohio 44106,2 Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030,3 Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 277104

Received 10 October 2007/ Returned for modification 24 October 2007/ Accepted 8 November 2007

Promyelocytic leukemia protein (PML) is an important regulator due to its role in numerous cellular processes including apoptosis, viral infection, senescence, DNA damage repair, and cell cycle regulation. Despite the role of PML in many cellular functions, little is known about the regulation of PML itself. We show that PML stability is regulated through interaction with the peptidyl-prolyl cis-trans isomerase Pin1. This interaction is mediated through four serine-proline motifs in the C terminus of PML. Binding to Pin1 results in degradation of PML in a phosphorylation-dependent manner. Furthermore, our data indicate that sumoylation of PML blocks the interaction, thus preventing degradation of PML by this pathway. Functionally, we show that in the MDA-MB-231 breast cancer cell line modulating levels of Pin1 affects steady-state levels of PML. Furthermore, degradation of PML due to Pin1 acts both to protect these cells from hydrogen peroxide-induced death and to increase the rate of proliferation. Taken together, our work defines a novel mechanism by which sumoylation of PML prevents Pin1-dependent degradation. This interaction likely occurs in numerous cell lines and may be a pathway for oncogenic transformation.

* Corresponding author. Mailing address: Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106. Phone: (216) 368-1150. Fax: (216) 368-3419. E-mail: hxk43{at}cwru.edu

{triangledown} Published ahead of print on 26 November 2007.

Molecular and Cellular Biology, February 2008, p. 997-1006, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01848-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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