Downregulation of Mitofusin 2 in Placenta Is Related to Preeclampsia

Background. Mitofusin 2 (Mfn2) is a novel mitochondrial protein that is implicated in cellular proliferation and metabolism; however, the role of Mfn2 in preeclampsia (PE) remains unknown. This study aimed to explore the relationship between Mfn2 and PE. Method. Preeclamptic and normal pregnancies were enrolled in a comparative study. The expression of Mfn2 in placenta was detected by qRT-PCR. And the mitochondrial function was detected by ATP assay. Then TEV-1 cells were cultured in hypoxic conditions. mRNA and protein expressions of Mfn2 were detected by qRT-PCR and western blot separately. Cells' viability was detected by MTT. And the mitochondrial function was detected by ATP and mitochondrial membrane potential (MMP) assay. We further knocked down the Mfn2 gene in TEV-1 cells and evaluated the cells' viability. Results. Mfn2 and ATP expressions were significantly decreased in preeclamptic placentae compared to normal placentae. Mfn2 expression level and the viability of TEV-1 cells were reduced during hypoxic conditions. TEV-1 cells' viability, ATP, and MMP levels were also significantly decreased after knockdown of the Mfn2 gene. Conclusions. These results suggest that defects in Mfn2 could cause mitochondrial dysfunction and decrease trophoblastic cells' viability. Therefore, Mfn2 may be functionally involved in the pathogenesis of PE

The tumor suppressive role of CAMK2N1 in castration-resistant prostate cancer.

Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. The CAMK2N1 gene, cloned and characterized as an inhibitor of CaMKII (calcium/calmodulin-dependent protein kinase II), has been shown to affect tumorigenesis and tumor growth. However, it is still unknown whether CAMK2N1 plays a role in prostate cancer development. We first examined the protein and mRNA levels of CAMK2N1 and observed a significant decrease in human prostate cancers comparing to normal prostate tissues. Re-expression of CAMK2N1 in prostate cancer cells reduced cellular proliferation, arrested cells in G0/G1 phases, and induced apoptotic cell death accompanied by down-regulation of IGF-1, ErbB2, and VEGF downstream kinases PI3K/AKT, as well as the MEK/ERK-mediated signaling pathways. Conversely, knockdown of CAMK2N1 had a significant opposite effects on these phenotypes. Our analyses suggest that CAMK2N1 plays a tumor suppressive role in prostate cancer cells. Reduced CAMK2N1 expression correlates to human prostate cancer progression and predicts poor clinical outcome, indicating that CAMK2N1 may serve as a biomarker. The inhibition of tumor growth by expressing CAMK2N1 established a role of CAMK2N1 as a therapeutic target

CAMK2N1 inhibits prostate cancer progression through androgen receptor-dependent signaling.

Castration resistance is a major obstacle to hormonal therapy for prostate cancer patients. Although androgen independence of prostate cancer growth is a known contributing factor to endocrine resistance, the mechanism of androgen receptor deregulation in endocrine resistance is still poorly understood. Herein, the CAMK2N1 was shown to contribute to the human prostate cancer cell growth and survival through AR-dependent signaling. Reduced expression of CAMK2N1 was correlated to recurrence-free survival of prostate cancer patients with high levels of AR expression in their tumor. CAMK2N1 and AR signaling form an auto-regulatory negative feedback loop: CAMK2N1 expression was down-regulated by AR activation; while CAMK2N1 inhibited AR expression and transactivation through CAMKII and AKT pathways. Knockdown of CAMK2N1 in prostate cancer cells alleviated Casodex inhibition of cell growth, while re-expression of CAMK2N1 in castration-resistant cells sensitized the cells to Casodex treatment. Taken together, our findings suggest that CAMK2N1 plays a tumor suppressive role and serves as a crucial determinant of the resistance of prostate cancer to endocrine therapies

WT1 Recruits TET2 to Regulate Its Target Gene Expression and Suppress Leukemia Cell Proliferation

The TET2 DNA dioxygenase regulates cell identity and suppresses tumorigenesis by modulating DNA methylation and expression of a large number of genes. How TET2, like most other chromatin modifying enzymes, is recruited to specific genomic sites is unknown. Here we report that WT1, a sequence-specific transcription factor, is mutated in a mutually exclusive manner with TET2, IDH1 and IDH2 in acute myeloid leukemia (AML). WT1 physically interacts with and recruits TET2 to its target genes to activate their expression. The interaction between WT1 and TET2 is disrupted by multiple AML-derived TET2 mutations. TET2 suppresses leukemia cell proliferation and colony formation in a manner dependent on WT1. These results provide a mechanism for targeting TET2 to specific DNA sequence in the genome. Our results also provide an explanation for the mutual exclusivity of WT1 and TET2 mutations in AML and suggest an IDH1/2-TET2-WT1 pathway in suppressing AML

Downregulation of Mitofusin 2 in Placenta Is Related to Preeclampsia

Background. Mitofusin 2 (Mfn2) is a novel mitochondrial protein that is implicated in cellular proliferation and metabolism; however, the role of Mfn2 in preeclampsia (PE) remains unknown. This study aimed to explore the relationship between Mfn2 and PE. Method. Preeclamptic and normal pregnancies were enrolled in a comparative study. The expression of Mfn2 in placenta was detected by qRT-PCR. And the mitochondrial function was detected by ATP assay. Then TEV-1 cells were cultured in hypoxic conditions. mRNA and protein expressions of Mfn2 were detected by qRT-PCR and western blot separately. Cells’ viability was detected by MTT. And the mitochondrial function was detected by ATP and mitochondrial membrane potential (MMP) assay. We further knocked down the Mfn2 gene in TEV-1 cells and evaluated the cells’ viability. Results. Mfn2 and ATP expressions were significantly decreased in preeclamptic placentae compared to normal placentae. Mfn2 expression level and the viability of TEV-1 cells were reduced during hypoxic conditions. TEV-1 cells’ viability, ATP, and MMP levels were also significantly decreased after knockdown of the Mfn2 gene. Conclusions. These results suggest that defects in Mfn2 could cause mitochondrial dysfunction and decrease trophoblastic cells’ viability. Therefore, Mfn2 may be functionally involved in the pathogenesis of PE

Multiple Sources of Indosinian Granites and Constraints on the Tectonic Evolution of the Paleo-Tethys Ocean in East Kunlun Orogen

Numerous Indosinian granitoids occur in the East Kunlun Orogen (EKO). The Indosinian was a key transitional period associated with the evolution of the Paleo-Tethys Ocean. Here, we study the relationship between the petrogenesis of the granitoids and the regional tectonic setting based on a comprehensive analysis of the petrology, geochronology, and geochemistry of typical granitoids in the eastern part of the EKO. The Indosinian granitoid compositions are dominated by quartz diorites, granodiorites, monzogranites, porphyritic monzogranites, and syenogranites. Early Indosinian granitoids are large, granitic batholiths, while the middle and late Indosinian granitoids are smaller in size. From the early Indosinian to late Indosinian, the granitoids show a transition from a medium-K calc-alkaline to high-K calc-alkaline composition. They are enriched in light rare earth elements (LREEs) and large-ion lithophile elements (LILEs) and depleted in high-field-strength elements (HFSEs), especially for the Helegangxilikete and the Kekeealong plutons. The late Indosinian granitoids have relatively low Y and Yb contents, high Sr contents, and high La/Yb and Sr/Y ratios, which suggests adakitic affinity. The zircon saturation temperatures of the early Indosinian syenogranite and the Keri syenogranite are above 800 °C. The zircon saturation temperatures of other Indosinian granites (average 749 °C) are lower than those of the biotite and amphibole partial melting experiment. In the early Indosinian (255–240 Ma), numerous granitoids were the products of the partial melting of the juvenile lower crust by mafic magma underplating. This underplating is geodynamically related to the continuous subduction of a branch of Paleo-Tethys Ocean, with slab break-off, rapid upwelling, and mantle decompression. In the middle Indosinian (240–230 Ma), the compression that accompanied the continent–continent collision was not conducive to fluid activity, and hence, the formation of magma could be attributed to dehydration partial melting of muscovite, biotite, or amphibole. In the late Indosinian (230–200 Ma), the delamination of thickened crust would provide heat and channels for fluid migration, leading to a flare-up of the magmas. The composition and petrogenesis of the Indosinian granitoids in the eastern EKO are the result of processes associated with the subduction, collisional, and post-collisional stages, during the evolution of the Paleo-Tethys Ocean