Transforming growth factor-beta (TGF-beta), is a negative regulator of epithelial cell growth via its ability to inhibit cell proliferation and/or induce apoptosis. The long term goal of the proposed studies is to determine whether deregulation of the TGF-beta signaling pathway, through which the biological signal is propagated, plays a significant role in initiation and progression of prostate cancer. We propose to use a human prostate tumorigenesis cell model system, the LNCaP cell line, in which specific loss of TGF-beta receptor type II function, is responsible for lack of responsivity to TGF-beta.
In Specific Aim 1, the LNCaP prostate cancer cells will be transfected with a plasmid encoding the R-II gene, to establish the relationship between over expression of TGF-beta receptor II and the tumorigenic behavior of these cells. Results from these studies will indicate whether restoration of TGF-beta sensitivity in LNCaP cells by over expression of a functional R-II receptor, leads to reversion of malignancy.
In Specific Aim 2 using R-II receptor overexpressing clones, we will investigate the potential downstream effectors that are essential for signaling/transducing the TGF-beta's antiproliferative and apoptotic effects. The expression of the cyclin-dependent kinase inhibitors, p21 WAF1/Cip1 and p27Kip1 and p16 will be examined in TGF-beta sensitive prostate cancer cells, after treatment with exogenous TGF- beta, by Northern and Western analysis, to determine whether deregulation of these potential effectors of the TGF-beta apoptotic signal occurs at a post-transcriptional or post-translational level.
In Specific Aim3, PCR and genetic sequencing techniques will be used to screen for the occurrence of mutations in the R-II receptor gene, that affect the receptor structure and function in prostate cancer cell lines that are weakly sensitive to TGF-beta. Results from these studies will be critical in identifying whether a dysfunctional TGF-beta mechanism is of major significance in prostate cancer development and progression, via loss of expression or genetic alterations of its transmembrane receptors R-I and R-II genes and deregulation of the downstream effectors that transduce TGF-beta apopoptic signal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK053525-01
Application #
2468847
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1997-09-01
Project End
2000-06-30
Budget Start
1997-09-01
Budget End
1998-06-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Surgery
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Zhu, Haining; Zhao, Jun; Zhu, Beibei et al. (2012) EMMPRIN regulates cytoskeleton reorganization and cell adhesion in prostate cancer. Prostate 72:72-81
Zhu, Brian; Zhai, Jianjun; Zhu, Haining et al. (2010) Prohibitin regulates TGF-beta induced apoptosis as a downstream effector of Smad-dependent and -independent signaling. Prostate 70:17-26
Pu, Hong; Collazo, Joanne; Jones, Elisabeth et al. (2009) Dysfunctional transforming growth factor-beta receptor II accelerates prostate tumorigenesis in the TRAMP mouse model. Cancer Res 69:7366-74
Zhu, Meng-Lei; Kyprianou, Natasha (2008) Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocr Relat Cancer 15:841-9
Schwarze, Steven R; Lin, Eric W; Christian, Perry A et al. (2008) Intracellular death platform steps-in: targeting prostate tumors via endoplasmic reticulum (ER) apoptosis. Prostate 68:1615-23
Zhu, Meng-Lei; Partin, James V; Bruckheimer, Elizabeth M et al. (2008) TGF-beta signaling and androgen receptor status determine apoptotic cross-talk in human prostate cancer cells. Prostate 68:287-95
Zhu, Beibei; Fukada, Kei; Zhu, Haining et al. (2006) Prohibitin and cofilin are intracellular effectors of transforming growth factor beta signaling in human prostate cancer cells. Cancer Res 66:8640-7
Reynolds, Arich Ryan; Kyprianou, Natasha (2006) Growth factor signalling in prostatic growth: significance in tumour development and therapeutic targeting. Br J Pharmacol 147 Suppl 2:S144-52
McKenzie, Shaun; Kyprianou, Natasha (2006) Apoptosis evasion: the role of survival pathways in prostate cancer progression and therapeutic resistance. J Cell Biochem 97:18-32
Zeng, L; Kyprianou, N (2005) Apoptotic regulators in prostatic intraepithelial neoplasia (PIN): value in prostate cancer detection and prevention. Prostate Cancer Prostatic Dis 8:7-13

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