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Characterization of the exome and genome of carcinoma (ccRCC) by next-generation sequencing identified numerous genetic alternations. BRCA1-associated protein-1 (BAP1) was identified as one of the most frequently mutated genes in ccRCC, suggesting that BAP1 is a potential key driver for ccRCC cancer initiation and progression. However, how BAP1 mutations contribute to ccRCC remains to be elucidated. BAP1 is a nuclear de-ubiquitinating enzyme and cleaves the ubiquitin chain from the substrates. Here, we identified MCRS1 as a bona fide substrate for BAP1. MCRS1 is a component of the centrosome proteins, and plays an essential role in spindle assembly. BAP1 binds to MCRS1 and stabilizes MCRS1 by de-ubiquitination. BAP1 contributes to chromosome stability partially via MCRS1. A positive correlation was identified between BAP1 and MCRS1 expression in ccRCC tissues. Both BAP1 loss and MCRS1 down-regulation in ccRCC were associated with adverse clinicopathological features. This study revealed a novel mechanism for BAP1 involved in MCRS1 stability regulation, and provided insight in understanding the relationship between BAP1 mutations and chromosome instability in ccRCC. [ABSTRACT FROM AUTHOR]

Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) is a multi-domain ubiquitin E3 ligase that plays critical roles in regulation of DNA methylation and histone ubiquitination. In this study, we found UHRF1 is frequently overexpressed in human clear cell Renal Cell Carcinoma (ccRCC) tissues both at mRNA and protein levels. We showed that UHRF1 directly interacts with p53 both in vivo and in vitro . A new domain (PD) in UHRF1 was required for interaction with p53. We found that UHRF1 down-regulates p53 transactivation activity which was depends on the ubiquitin E3 ligase function. UHRF1 can promote non-degradative ubiquitination of p53, suppress p53 pathway activation and p53-dependent apoptosis in ccRCC cells. Together, our study suggests that UHRF1, which overexpressed ccRCC, may act as a p53 regulator, suppress p53 pathway activation and help ccRCC cells to escape from p53-dependent apoptosis. [ABSTRACT FROM AUTHOR]

Iliac atherosclerosis is common in renal transplant recipients. In severe cases, it affects intraoperative renal arterial anastomosis and increases the risk of postanastomosis complications. At present, safe and efficient vascular replacement methods are relatively limited. In the 2 renal transplant cases at our center, described here, the donors' iliac arteries were unavailable. We therefore attempted to replace the recipients' diseased external iliac artery with the donors' inferior vena cava and then performed an end-to-side grafting with the attachment in arterial reconstruction. One patient received a single kidney transplantation, while the other received a dual kidney transplantation. Antiplatelet/anticoagulation drug application was avoided, and both patients were observed for more than 6 months. Stable renal graft function was achieved without any vascular complications. During this study, all procedures were in compliance with the Helsinki Congress and the Declaration of Istanbul. For end-stage renal disease patients with severe iliac atherosclerosis who are waiting for kidney transplantation, a donor's vena cava graft could potentially be a promising replacement option to restore external iliac artery patency and reconstruct renal blood flow, without the necessity of harvesting a recipient's autologous vessels or looking for costly artificial ones. [ABSTRACT FROM AUTHOR]

• TSLP/TSLPR signaling was activated in human and mice renal fibrosis. • Tubule cell-derived TSLP could promote the activation of renal fibroblast via TSLPR-STAT3 signaling pathway. • Inhibition of the TSLP/TSLPR axis could relieve renal fibrosis in-vivo. Previous studies have demonstrated the importance of TSLP-TSLPR in inflammatory, allergic, and fibrotic diseases. However, their exact molecular mechanism in regulating renal fibrosis has not been fully explored yet. The current study identified the high expression levels of TSLP and TSLPR in human and mouse hydronephrotic tissues. In addition, immunofluorescence staining showed that TSLP was highly expressed in renal tubular cells, while TSLPR was mainly co-localized with α-SMA, a marker of fibroblasts. Knocking out TSLPR in the UUO model could alleviate the severity of renal fibrosis. Most importantly, the application of antibody blockade of TSLP reduced the fibrotic level in the UUO model. The functional analysis revealed that the hypoxic exposure could induce the overexpression of TSLP in renal tubular cells via HIF-1α. The tubular cell-derived TSLP could bind to the TSLPR of fibroblasts in a paracrine manner to activate them. Specifically, the HIF-1α/TSLP/TSLPR-axis could activate fibroblasts through the STAT3 signaling pathway. This study revealed a mechanistic interaction of HIF-1α/TSLP/TSLPR and STAT3 signaling pathways in the activation and proliferation of human and murine kidney fibroblasts; these pathways might be exploited as a therapeutic target in renal fibrosis. [ABSTRACT FROM AUTHOR]

Background: Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alterations. SPOP (Speckle-type POZ Protein) is one of the most frequently mutated genes in primary prostate cancer, suggesting that SPOP may be a potential driver of prostate cancer. The aim of this work was to investigate how SPOP mutations contribute to prostate cancer development and progression. Methods: To identify molecular mediators of the tumor suppressive function of SPOP, we performed a yeast two-hybrid screen in a HeLa cDNA library using the full-length SPOP as bait. Immunoprecipitation and Western Blotting were used to analyze the interaction between SPOP and ATF2. Cell migration and invasion were determined by Transwell assays. Immunohistochemistry were used to analyze protein levels in patients' tumor samples. Results: Here we identified ATF2 as a bona fide substrate of the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP recognizes multiple Ser/Thr (S/T)-rich degrons in ATF2 and triggers ATF2 degradation via the ubiquitin-proteasome pathway. Strikingly, prostate cancer-associated mutants of SPOP are defective in promoting ATF2 degradation in prostate cancer cells and contribute to facilitating prostate cancer cell proliferation, migration and invasion. Conclusion: SPOP promotes ATF2 ubiquitination and degradation, and ATF2 is an important mediator of SPOP inactivation-induced cell proliferation, migration and invasion. [ABSTRACT FROM AUTHOR]

Natural products have become sources of developing new drugs for the treatment of cancer. To seek candidate compounds that inhibit the growth of liver cancer, components of Chloranthus serratus were tested. Here, we report that shizukaol D, a dimeric sesquiterpene from Chloranthus serratus, exerted a growth inhibition effect on liver cancer cells in a dose- and time-dependent manner. We demonstrated that shizukaol D induced cells to undergo apoptosis. More importantly, shizukaol D attenuated Wnt signalling and reduced the expression of endogenous Wnt target genes, which resulted in decreased expression of β-catenin. Collectively, this study demonstrated that shizukaol D inhibited the growth of liver cancer cells by modulating Wnt pathway. [ABSTRACT FROM AUTHOR]

HDGFRP2 (HRP-2) belongs to the Hepatoma-derived growth factor (HDGF)-related proteins (HRPs) family, which are characterized by a conserved HATH/PWWP domain at a well-conserved region of the N-terminus. However, the cellular function of HRP-2 remains unknown. In this study, we showed for the first time that HRP-2 is frequently overexpressed in human HCC tissues at mRNA and protein levels. We further showed that HRP-2 can promote HCC cells growth in vitro and xenograft tumors in vivo. Using protein affinity purification methods, we searched for functional partners of HRP-2, and found that HRP-2 interacts with various proteins known to be involved in transcription elongation and processing. Furthermore, we demonstrate HRP-2 interacts and co-localizes with RNA processing regulator IWS1, and positively regulated the mRNA level of Cyclin D1. Together, our study suggests HRP-2 may act as an mRNA processing co-factor to promote cells growth by regulating the mRNA of key oncogenes, which can be explored further for cancer treatment. [ABSTRACT FROM AUTHOR]

Centrosome linker tethers interphase centrosomes together allowing them to function as a single microtubule organization center. The centrosome linker is disrupted at the onset of mitosis to ensure timely centrosome disjunction and bipolar spindle formation and is reassembled at the end of mitosis. While the mechanism controlling centrosome linker disassembly at early mitosis has been well explored, little is known about how the linker is subsequently reassembled before mitotic exit. Here we report that ASPP1 and ASPP2, two members of the apoptosis stimulating proteins of p53 (ASPP) family, are involved in centrosome linker reassembly. We showed that ASPP1/2 interacted with centrosome linker protein C-Nap1. Co-depletion of ASPP1 and ASPP2 inhibited re-association of C-Nap1 with centrosome at the end of mitosis. Moreover, ASPP1/2 facilitated the interaction between C-Nap1 and PP1α, and this interaction was significantly reduced by co-depletion of ASPP1/2. ASPP1/2 antagonized the NEK2A-mediated C-Nap1 Ser2417/2421 phosphorylation in a PP1-dependent manner. Co-depletion of ASPP1 and ASPP2 inhibited dephosphorylation of C-Nap1 (Ser2417/2421) at the end of mitosis. Based on these findings, we propose that ASPP1/2 act as PP1-targeting subunits to facilitate C-Nap1 dephosphorylation and centrosome linker reassembly at the end of mitosis. [ABSTRACT FROM AUTHOR]

ASPP2 is an important tumor suppressor protein promoting p53-dependent and-independent apoptosis. However, it has been unclear how ASPP2 protein is regulated. Here, we identified Itch as the E3 ubiquitin ligase for ASPP2. Itch interacts with ASPP2 and mediates its degradation and ubiquitination in vivo. The PPXY motif of ASPP2 interacts with the WW domains of Itch. Yap1 competes with Itch for binding to ASPP2, and prevents Itch-mediated degradation and ubiquitination of ASPP2. Together, these observations reveal that Itch and Yap1 have antagonistic roles in the regulation of ASPP2 protein stability through competing post-translational regulatory mechanism of ASPP2. [ABSTRACT FROM AUTHOR]