Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset form of Parkinson's disease characterized by motor disturbances and dopaminergic neurodegeneration. To address its underlying molecular pathogenesis, we generated and characterized loss-of-function mutants of Drosophila PTEN-induced putative kinase 1 (PINK1), a novel AR-JP-linked gene. Here, we show that PINK1 mutants exhibit indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Furthermore, transmission electron microscopy analysis and a rescue experiment with Drosophila Bcl-2 demonstrated that mitochondrial dysfunction accounts for the degenerative changes in all phenotypes of PINK1 mutants. Notably, we also found that PINK1 mutants share marked phenotypic similarities with parkin mutants. Transgenic expression of Parkin markedly ameliorated all PINK1 loss-of-function phenotypes, but not vice versa, suggesting that Parkin functions downstream of PINK1. Taken together, our genetic evidence clearly establishes that Parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons.

Synoviolin, also called HRD1, is an E3 ubiquitin ligase and is implicated in endoplasmic reticulum -associated degradation. In mammals, Synoviolin plays crucial roles in various physiological and pathological processes, including embryogenesis and the pathogenesis of arthropathy. However, little is known about the molecular mechanisms of Synoviolin in these actions. To clarify these issues, we analyzed the profile of protein expression in synoviolinnull cells. Here, we report that Synoviolin targets tumor suppressor gene p53 for ubiquitination. Synoviolin sequestrated and metabolized p53 in the cytoplasm and negatively regulated its cellular level and biological functions, including transcription, cell cycle regulation and apoptosis. Furthermore, these p53 regulatory functions of Synoviolin were irrelevant to other E3 ubiquitin ligases for p53, such as MDM2, Pirh2 and Cop1, which form autoregulatory feedback loops. Our results provide novel insights into p53 signaling mediated by Synoviolin.

Curcumin has become a focus of interest with regard to its antitumor effects in prostate cancer; however, the effects of this agent on invasion and metastasis remain less well understood. Matrix metalloproteinases (MMPs) are important prerequisite for tumor invasion and metastasis. In this study, we evaluated the effects of curcumin on prostate cancer cells (DU-145) invasion in both in vitro and in vivo. We utilized zymography and ELISA in order to determine the MMP-2 and MMP-9 activity. Matrigel invasion assay was performed to assess cellular invasion. We developed a xenograft model to examine tumorigenicity. Curcumin treatment resulted not only in a significant reduction in the expression of MMP-2 and MMP-9, but also effected the inhibition of invasive ability in vitro. Curcumin was shown to induce a marked reduction of tumor volume, MMP-2, and MMP-9 activity in the tumor-bearing site. The metastatic nodules in vivo were significantly fewer in the curcumintreated group than untreated group. Curcumin appears to constitute a potential agent for the prevention of cancer progression, or at least of the initial phase of metastasis, in prostate cancer.

Hypoxia-induced MMP-3 expression is exclusively regulated by HIF-1alpha, and hypoxia-induced MMP-1 or IL-8 expression appears to have salvage pathways other than the HIF-1alpha pathway. Together, these data provide new insight regarding the mechanism by which hypoxia participates in joint inflammation and destruction in RA.