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Title page for ETD etd-08302007-113157

Type of Document Dissertation
Author Ghosh, Ritwik
Author's Email Address ritwik.ghosh@vanderbilt.edu
URN etd-08302007-113157
Title Stathmin Mediated Tumor Progression Through Androgens And TGF-beta Signaling
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Robert Matusik Committee Chair
Neil Bhowmick Committee Member
Robert Coffey Committee Member
Susan Kasper Committee Member
  • Transforming growth factors-beta
  • Prostate Cancer
  • Stathmin
  • Epithelial-to-Mesenchymal Transition
  • Phosphoprotieins -- Mechanism of action
Date of Defense 2007-08-07
Availability unrestricted

Prostate proliferation is highest during development and tumorigenesis. We postulate that proteins which regulate normal prostate growth also promote prostate cancer (PCa) progression. Two Dimensional Gel Electrophoresis was utilized to compare patterns of protein expression in 12T-7f prostates (LPB-Tag mouse model for PCa) during tumor development and progression with those of normal developing and adult wild type CD-1 prostates. Stathmin expression and phosphorylation patterns were analyzed in mouse and human PCa cell lines as well as in human PCa tissue arrays. Stathmin was identified by two-dimensional gel electrophoresis and mass spectrometry. Stathmin levels increase early during normal mouse prostate development and again during prostate tumor development and progression. In human prostate adenocarcinoma, stathmin increases in Gleason pattern 5. Further, stathmin is differentially phosphorylated in androgen-dependent LNCaP cells compared to androgen-independent PC-3 and DU145 cells. This differential phosphorylation is modulated by androgen and anti-androgen treatment.

We have identified stathmin as a regulator of epithelial cell homeostasis. Knocking down stathmin expression using RNAi technology resulted in epithelial-to-mesenchymal transitional cells (EMT) within 24 hours and without TGF-beta treatment. Our results indicate that stathmin blocks p38MAPK phosphorylation, thereby promoting E-cadherin expression and juxta-membrane localization while suppressing vimentin expression. Moreover, blocking phosphorylation of p38MAPK in stathmin siRNA-transfected DU145 or expressing stathmin in stathmin-negative NMuMG cells prevents the emergence of EMT despite TGF-beta1 treatment.

In summary, we propose that stathmin functions as a gatekeeper in maintaining a normal epithelial cell phenotype. Stathmin exhibits differential function in normal compared to cancer cells, similar to the duel roles of TGF-beta as a tumor suppressor in normal cells and a tumor promoter at later stages of cancer progression. Stathmin over-expression has been associated with a number of different cancers including leukemia as well as breast, ovarian and prostate cancer. On the other hand, mechanisms, which disrupt stathmin expression, such as activation of TGF-beta1 signaling, result in destabilization of the cytoskeletal framework of the epithelial cell and progression to EMT. Thus, stathmin represents an attractive target for therapeutic intervention aimed at maintaining a normal epithelial phenotype and controlling tumor spread.

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  01ThesisTitle-Page.pdf 47.85 Kb 00:00:13 00:00:06 00:00:05 00:00:02 < 00:00:01
  02Thesis-Front-Pages.pdf 113.20 Kb 00:00:31 00:00:16 00:00:14 00:00:07 < 00:00:01
  03Chapter-I.pdf 1.10 Mb 00:05:05 00:02:37 00:02:17 00:01:08 00:00:05
  04Chapter-II.pdf 163.66 Kb 00:00:45 00:00:23 00:00:20 00:00:10 < 00:00:01
  05Chapter-III.pdf 2.68 Mb 00:12:23 00:06:22 00:05:34 00:02:47 00:00:14
  06Chapter-IV.pdf 8.78 Mb 00:40:38 00:20:53 00:18:17 00:09:08 00:00:46
  07Chapter-V.pdf 8.81 Mb 00:40:47 00:20:58 00:18:21 00:09:10 00:00:46
  08Chapter-VI.pdf 15.83 Mb 01:13:16 00:37:40 00:32:58 00:16:29 00:01:24
  09Chapter-VII.pdf 142.50 Kb 00:00:39 00:00:20 00:00:17 00:00:08 < 00:00:01
  10References.pdf 229.63 Kb 00:01:03 00:00:32 00:00:28 00:00:14 00:00:01

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