Faculty Collaboration Database

Overexpression of transforming growth factor β1 in malignant prostate cells is partly caused by a runaway of TGF-β1 auto-induction mediated through a defective recruitment of protein phosphatase 2A by TGF-β type I receptor. Urology 2010 Dec;76(6):1519.e8-13

Date

10/30/2010

Pubmed ID

21030067

Pubmed Central ID

PMC2997920

DOI

10.1016/j.urology.2010.03.061

Scopus ID

2-s2.0-78649903609 (requires institutional sign-in at Scopus site)   28 Citations

Abstract

OBJECTIVES: To elucidate the mechanism of transforming growth factor (TGF)-β1 overexpression in prostate cancer cells.

METHODS: Malignant (PC3, DU145) and benign (RWPE1, BPH1) prostate epithelial cells were used. Phosphatase activity was measured using a commercial kit. Recruitment of the regulatory subunit, Bα, of protein phosphatase 2A (PP2A-Bα) by TGF-β type I receptor (TβRI) was monitored by coimmunoprecipitation. Blockade of TGF-β1 signaling in cells was accomplished either by using TGF-β-neutralizing monoclonal antibody or by transduction of a dominant negative TGF-β type II receptor retroviral vector.

RESULTS: Basal levels of TGF-β1 in malignant cells were significantly higher than those in benign cells. Blockade of TGF-β signaling resulted in a significant decrease in TGF-β1 expression in malignant cells, but not in benign cells. Upon TGF-β1 treatment (10 ng/mL), TGF-β1 expression was increased in malignant cells, but not in benign cells. This differential TGF-β1 auto-induction between benign and malignant cells correlated with differential activation of extracellular signal-regulated kinase (ERK). Following TGF-β1 treatment, the activity of serine/threonine phosphatase and recruitment of PP2A-Bα by TβRI increased in benign cells, but not in malignant cells. Inhibition of PP2A in benign cells resulted in an increase in ERK activation and in TGF-β1 auto-induction after TGF-β1 (10 ng/mL) treatment.

CONCLUSIONS: These results suggest that TGF-β1 overexpression in malignant cells is caused, at least in part, by a runaway of TGF-β1 auto-induction through ERK activation because of a defective recruitment of PP2A-Bα by TβRI.

Author List

Yu N, Kozlowski JM, Park II, Chen L, Zhang Q, Xu D, Doll JA, Crawford SE, Brendler CB, Lee C

Author

Jennifer A. Doll PhD Assistant Professor in the Biomedical Sciences department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Autocrine Communication
Cell Line, Tumor
Enzyme Activation
Gene Expression Regulation, Neoplastic
Humans
Male
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Neoplasm Proteins
Phosphorylation
Prostate
Prostatic Neoplasms
Protein Phosphatase 2
Protein Processing, Post-Translational
RNA, Messenger
RNA, Neoplasm
Receptors, Transforming Growth Factor beta
Reverse Transcriptase Polymerase Chain Reaction
Transforming Growth Factor beta1