Prolyl isomerase Pin1 downregulates tumor suppressor RUNX3 in breast cancer.

Abstract	Emerging evidence demonstrates that RUNX3 is a tumor suppressor in breast cancer. Inactivation of RUNX3 in mice results in spontaneous mammary gland tumors, and decreased or silenced expression of RUNX3 is frequently found in breast cancer cell lines and human breast cancer samples. However, the underlying mechanism for initiating RUNX3 inactivation in breast cancer remains elusive. Here, we identify prolyl isomerase Pin1, which is often overexpressed in breast cancer, as a key regulator of RUNX3 inactivation. In human breast cancer cell lines and breast cancer samples, expression of Pin1 inversely correlates with the expression of RUNX3. In addition, Pin1 recognizes four phosphorylated Ser/Thr-Pro motifs in RUNX3 via its WW domain. Binding of Pin1 to RUNX3 suppresses the transcriptional activity of RUNX3. Furthermore, Pin1 reduces the cellular levels of RUNX3 in an isomerase activity-dependent manner by inducing the ubiquitination and proteasomal degradation of RUNX3. Knocking down Pin1 enhances the cellular levels and transcriptional activity of RUNX3 by inhibiting the ubiquitination and degradation of RUNX3. Our results identify Pin1 as a new regulator of RUNX3 inactivation in breast cancer.
Authors	Y-H Nicole Tsang, X-W Wu, J-S Lim, C Wee Ong, M Salto-Tellez, K Ito, Y Ito, L-F Chen
Journal	Oncogene (Oncogene) Vol. 32 Issue 12 Pg. 1488-96 (Mar 21 2013) ISSN: 1476-5594 [Electronic] England
PMID	22580604 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Core Binding Factor Alpha 3 Subunit NIMA-Interacting Peptidylprolyl Isomerase Runx3 protein, human Tumor Suppressor Proteins PIN1 protein, human Peptidylprolyl Isomerase Pin1 protein, mouse
Topics	Amino Acid Motifs Breast Neoplasms (metabolism, pathology) Cell Line, Tumor Core Binding Factor Alpha 3 Subunit (analysis, chemistry, genetics, physiology) Down-Regulation Female Humans NIMA-Interacting Peptidylprolyl Isomerase Peptidylprolyl Isomerase (analysis, physiology) Phosphorylation Protein Stability Tumor Suppressor Proteins Ubiquitination

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