| Popis: |
Hydrogen peroxide-inducible clone-5 (Hic-5, or androgen receptor-associated protein 55) has been implicated in prostate cancer progression. Recent studies from our laboratory have reported that Hic-5 modulates transforming growth factor-β (TGF-β) signaling by inactivating Smad3 and Smad7. In this study, we explored the role of Hic-5 in another arm of the TGF-β superfamily, namely bone morphogenetic protein (BMP) signaling, because BMP aberrations were identified in prostate cancer. In particular, we focused on the effect of Hic-5 on BMP4-induced activations of Smads 1, 5 & 8 in the prostate. We showed that Hic-5 binds and inhibits Smads 1, 5 & 8 functions by interacting with its MH2 domain. We also presented that Hic-5 possesses the ability to inhibit BMP4-induced apoptosis and promote cell survival. Moreover, the binding of Hic-5 with Smad1 at the endogenous level and the identification of Smad1 as the mediator of BMP4-induced apoptosis were demonstrated, further suggesting that Hic-5 blocks BMP4-induced apoptosis through inactivating Smad1. These results collectively characterize the role of Hic-5 as an anti-apoptotic and cell survival promoter, which are important hallmarks of cancer. The characterization of the LIM3 domain of Hic-5 involved in binding with Smad1 implicates a possible therapeutic target for reversing the effect of Hic-5.To study the roles of Hic-5 in vivo, a Hic-5 conditional knockout (cko) mouse model will be generated in collaboration with Dr. Seong-Jin Kim’s lab. Studies have shown that Hic-5 expression appears to be restricted to the stromal components of normal prostate, and functions as a tumor suppressor by inhibiting growth factor expression in prostate stromal cells and maintains homeostasis, thus disfavoring tumorigenesis. Loss of Hic-5 expression in the stroma could promote prostate cancer by releasing mitogens for the epithelial components of the prostate. On the other hand, ectopic expression of Hic-5 in the prostate epithelium may be tumor promoting by inhibiting TGF-β induced apoptosis and activating epithelial-mesenchymal transition (EMT). The generation of Hic-5 cko mice may help us better understand the equivocal nature of Hic-5 in the development of prostate tumorigenesis. |
