TGF-Beta Induction of PMEPA1: Role in Bone Metastasis Due to Prostate Cancer
Annual summary rept. 15 Dec 2006-14 Dec 2008
VIRGINIA UNIV CHARLOTTESVILLE
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TGF--beta provided by the bone microenvironment is a key factor in the development of bone metastases. Previous experiments have demonstrated that interference with TGF-beta signaling in cancer cells decreases the development of bone metastases. TGF-beta stimulates prostate cancer cell signaling and alters their phenotype. TGF-beta signaling in cancer is however complex and can lead to the activation of numerous genes. We identified PMEPA1 as the most highly upregulated gene by TGF-beta in PC-3 cells and little is known about its function in cells. We have shown that the absence of PMEPA1 in prostate cancer cells increases bone metastases from prostate cancer in a mouse model. This result is consistent with in vitro experiments showing that the membrane-bound isoform PMEPA1a decreases TGF-beta signaling via its interaction with E3 ubiquitin ligase and Smad protein, which suggest that membrane-bound PMEPA1 target Smad protein for proteosomal degradation. Interestingly the cytosolic isoform of PMEPA1, which is also induced by TGF-beta, prevented PMEPA1a to inhibit TGF-beta signaling. It is possible that PMEPA1c compete with PMEPA1a to bind Smads. Their different localization in cells could then explain their different properties. These results suggest that depending on which isoform is the most abundant in cells, PMEPA1 can provide a positive or negative feedback loop for TGF-beta signaling.
- Anatomy and Physiology
- Medicine and Medical Research