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

Abstract

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.

ACKNOWLEDGMENTS

We thank D. Samols and M. Snider for their comments on the manuscript. We thank Ron Evans and Hsiu-Ming Shih for reagents.

H.-Y. Kao is a recipient of the James T. Pardee-Carl A. Gerstacker Assistant of Cancer Research Faculty Chair in Cancer Research at CWRU Cancer Center and an American Cancer Society Research Scholar (RSG-04-052-01-GMC). This research was supported by the Aging Cancer Research Program at the Case Comprehensive Cancer Center (P20 CA103736), the Confocal Microscopy Core Facility of the Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland (P30 CA43703-12), an NIH grant to A.R.M. (CA082845), and an NIH grant to K.-S.C. (CA055577). E.L.R. is supported by a Case Comprehensive Cancer Center NIH/NCI Research Oncology Training Grant (T32 CA059366-11). K.J.S. is supported by an NIH cellular and molecular biology training grant (T32 GM08056).