Hypoxia-inducible factor-1alpha (HIF1alpha) is a central regulator of the cellular response to hypoxia. Prolyl-hydroxylation of HIF1alpha by PHD enzymes is prerequisite for HIF1alpha degradation. Here, we demonstrate that the abundance of PHD1 and PHD3 are regulated via their targeting for proteasome-dependent degradation by the E3 ubiquitin ligases Siah1a/2, under hypoxia conditions. Siah2 null fibroblasts exhibit prolonged PHD3 half-life, resulting in lower levels of HIF1alpha expression during hypoxia. Significantly, hypoxia-induced HIF1alpha expression was completely inhibited in Siah1a/2 null cells, yet could be rescued upon inhibition of PHD3 by RNAi. Siah2 targeting of PHD3 for degradation increases upon exposure to even mild hypoxic conditions, which coincides with increased Siah2 transcription. Siah2 null mice subjected to hypoxia displayed an impaired hyperpneic respiratory response and reduced levels of hemoglobin. Thus, the control of PHD1/3 by Siah1a/2 constitutes another level of complexity in the regulation of HIF1alpha during hypoxia.
TRAF2 is a RING finger protein that regulates the cellular response to stress and cytokines by controlling JNK, p38 and NF-jB signaling cascades. Here, we demonstrate that TRAF2 ubiquitination is required for TNFa-induced activation of JNK but not of p38 or NF-jB. Intact RING and zinc finger domains are required for TNFa-induced TRAF2 ubiquitination, which is also dependent on Ubc13. TRAF2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of JNK. Inhibition of Ubc13 expression by RNAi resulted in inhibition of TNFa-induced TRAF2 translocation and impaired activation of JNK but not of IKK or p38. TRAF2 aggregates in the cytoplasm, as seen in HodgkinReed-Sternberg lymphoma cells, resulting in constitutive NF-jB activity but failure to activate JNK. These findings demonstrate that the TRAF2 RING is required for Ubc13-dependent ubiquitination, resulting in translocation of TRAF2 to an insoluble fraction and activation of JNK, but not of p38 or NF-jB. Altogether, our findings highlight a novel mechanism of TRAF2-dependent activation of diverse signaling cascades that is impaired in HodgkinReed-Sternberg cells.
The variability in measurements of complex permittivities of tumor tissues between multiple samples could be attributed to the volume fraction of cancer cells in the excised tumor tissue. By the use of a digital photomicrograph image and hematoxylin-eosin staining, it was found that the malignant tumor tissue was not fully occupied by the cancer cells, but the cells were distributed locally in the stroma cells depending on the growth of cancer. The results showed that the volume fraction of cancer cells in the tumor tissue had a correlation to the measured conductivity and dielectric constant in the frequency range from 1 GHz to 6 GHz. It introduces a method to understand and gauge variability in measurements between different tumors.
Axam has been identified as a novel Axin-binding protein that inhibits the Wnt signaling pathway. We studied the molecular mechanism by which Axam stimulates the downregulation of -catenin.
In this report, a hand-held impulse-radar breast cancer detector is presented and the detectability of malignant breast tumors is demonstrated in the clinical test at Hiroshima University Hospital, Hiroshima, Japan. The core functional parts of the detector consist of 65-nm technology complementary metal-oxide-semiconductor (CMOS) integrated circuits covering the ultrawideband width from 3.1 to 10.6 GHz, which enable the generation and transmission of Gaussian monocycle pulse (GMP) with the pulse width of 160 ps and single port eight throw (SP8T) switching matrices for controlling the combination of 4 × 4 cross-shaped dome antenna array. The detector is designed to be placed on the breast with the patient in the supine position. The detectability of malignant tumors is confirmed in excised breast tissues after total mastectomy surgery. The three-dimensional positions of the tumors in the imaging results are consistent with the results of histopathology analysis. The clinical tests are conducted by a clinical doctor for five patients at the hospital. The malignant tumors include invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS). The final confocal imaging results are consistent with those of Magnetic Resonance Imaging (MRI), demonstrating the feasibility of the hand-held impulse-radar detector for malignant breast tumors.
Postoperative prognosis is better for hormonal receptor-positive breast cancer than for other phenotypes; however, there are no definitive predictive factors for relapse or survival. This study aimed to evaluate the maximum standardized uptake value (SUVmax) on 18F-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) and clinicopathological characteristics as possible predictors of postoperative relapse-free survival (RFS) and overall survival (OS) in hormonal receptor-positive breast cancer patients. We evaluated 262 patients with Stage I–III breast cancer diagnosed as luminal type (luminal A, 166; luminal B, 96 patients) who underwent preoperative FDG-PET/CT between January 2006 and December 2011 at two institutions. The relationships among SUVmax and clinicopathological factors (age, clinical T/N stage, nuclear grade, lymph node metastasis and vascular invasion) were evaluated. A phantom study was performed to correct differences in PET/CT analysis between two institutions. The patients were divided according to the SUVmax cutoff on receiver operating characteristic (ROC) analysis for OS (≤6.0 group vs. >6.0 group, AUC = 0.742). Clinical T-factor and nuclear grade were significantly correlated with SUVmax (p < 0.0001 and p = 0.0092, respectively). In the uni- and multivariate analyses using the Cox model for relapse, SUVmax was significant (p = 0.013 and p = 0.055, respectively) among characteristics. RFS curves showed that prognosis was significantly better for the SUVmax ≤ 6.0 group than for the SUVmax > 6.0 group (p = 0.004). Similarly, SUVmax was significant for OS (p = 0.007 and p = 0.008). OS was significantly different between the SUVmax ≤ 6.0 and >6.0 groups (p < 0.001). SUVmax was useful for predicting outcomes in patients with luminal-type breast cancer.
Clearance of misfolded proteins by endoplasmic reticulum (ER)-associated degradation (ERAD) requires concerted activity of chaperones, adaptor proteins, ubiquitin ligases, and proteasomes. RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins. Among RNF5-associated proteins is JNK-associated membrane protein (JAMP), a 7-transmembrane protein located within the ER membrane that facilitates degradation of misfolded proteins through recruitment of proteasomes and ERAD regulatory components. Here we demonstrate that RNF5 associates with JAMP in the ER membrane. This association results in Ubc13-dependent RNF5-mediated noncanonical ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but rather inhibits its association with Rpt5 and p97. Consequently, clearance of misfolded proteins, such as CFTR⌬508 and T cell receptor ␣, is less efficient, resulting in their greater accumulation. Significantly, the RNF5 effect on JAMP is seen prior to and after ER stress response, thereby highlighting a novel mechanism to limit ERAD and proteasome assembly at the ER, to the actual ER stress response.Degradation of misfolded proteins is part of a complex quality control system that clears diverse proteins independent of sequence or functional similarity (1-3). The unfolded protein response reduces the burden caused by unfolded protein accumulation in the endoplasmic reticulum (ER) 2 (4), in part by activating its key regulatory proteins IRE1-XBP1 and ATF6, which results in transcriptional activation of genes important for unfolded protein response, including components of the ER-associated degradation system (ERAD) (5).ERAD is regulated by an ER quality control system that marks proteins that cannot fold or assemble into multiprotein complexes for ubiquitin-dependent degradation (1-3). This system consists of molecular chaperones such as BiP (1-3), which interacts with misfolded protein to enable their transfer across the ER membrane via the multispanning membrane proteins Derlin-1/2/3 and Sec61(6), and the AAA (ATPase p97 (also known as VCP or cdc48)). Subsequent to translocation, misfolded proteins are ubiquitinated via ERanchored ubiquitin ligases, such as the vertebrate gp78, Parkin, RNF5/RMA1, and Hrd1 (7-10), followed by proteasome-mediated degradation.RNF5 (RING finger domain E3 ligase; also known as RMA1) is one of the few ER-associated E3 ubiquitin ligases. Anchored to the ER membrane via its C terminus, RNF5 consists of a classic RING domain (which confers ligase activity), a single transmembrane-spanning domain located within the C-terminal region, and a formin-like homology domain. RNF5 has been shown to promote degradation of misfolded proteins, such as mutant CFTR (CFTR⌬508) (9, 10). Intriguingly, RNF5-mediated degradation of mutant CFTR requires cooperation with another ligase, as has also been shown for gp78 or CHIP, suggesting a two-stage process in which the first ligase promotes substrate mono-ubiquitination, whereas the second media...
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