The structure and regulation of Cullin 2 based E3 ubiquitin ligases and their biological functions.

BACKGROUND: Cullin-RING E3 ubiquitin ligase complexes play a central role in targeting cellular proteins for ubiquitination-dependent protein turnover through 26S proteasome. Cullin-2 is a member of the Cullin family, and it serves as a scaffold protein for Elongin B and C, Rbx1 and various substrate recognition receptors to form E3 ubiquitin ligases. MAIN BODY OF THE ABSTRACT: First, the composition, structure and the regulation of Cullin-2 based E3 ubiquitin ligases were introduced. Then the targets, the biological functions of complexes that use VHL, Lrr-1, Fem1b, Prame, Zyg-11, BAF250, Rack1 as substrate targeting subunits were described, and their involvement in diseases was discussed. A small molecule inhibitor of Cullins as a potential anti-cancer drug was introduced. Furthermore, proteins with VHL box that might bind to Cullin-2 were described. Finally, how different viral proteins form E3 ubiquitin ligase complexes with Cullin-2 to counter host viral defense were explained. CONCLUSIONS: Cullin-2 based E3 ubiquitin ligases, using many different substrate recognition receptors, recognize a number of substrates and regulate their protein stability. These complexes play critical roles in biological processes and diseases such as cancer, germline differentiation and viral defense. Through the better understanding of their biology, we can devise and develop new therapeutic strategies to treat cancers, inherited diseases and viral infections

Loss of 4E-BP1 Function Induces EMT and Promotes Cancer Cell Migration and Invasion via Cap-Dependent Translational Activation of Snail

The cap-dependent translation is frequently deregulated in a variety of cancers associated with tumor progression. However, the molecular basis of the translation activation for metastatic progression of cancer remains largely elusive. Here, we demonstrate that activation of cap-dependent translation by silencing the translational repressor 4E-BP1 causes cancer epithelial cells to undergo epithelial-mesenchymal transition (EMT), which is associated with selective upregulation of the EMT inducer Snail followed by repression of E-cadherin expression and promotion of cell migratory and invasive capabilities as well as metastasis. Conversely, inhibition of cap-dependent translation by a dominant active mutant 4E-BP1 effectively downregulates Snail expression and suppresses cell migration and invasion. Furthermore, dephosphorylation of 4E-BP1 by mTORC1 inhibition or directly targeting the translation initiation also profoundly attenuates Snail expression and cell motility, whereas knockdown of 4E-BP1 or overexpression of Snail significantly rescues the inhibitory effects. Importantly, 4E-BP1-regulated Snail expression is not associated with its changes in the level of transcription or protein stability. Together, these findings indicate a novel role of 4E-BP1 in the regulation of EMT and cell motility through translational control of Snail expression and activity, and suggest that targeting cap-dependent translation may provide a promising approach for blocking Snail-mediated metastatic potential of cancer

Retrieval of atmospheric trace gases from satellite infrared limb sounding data

The Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) instrument which operated in the near-to-mid infrared on the Envisat satellite from 2002– 2012 is a Fourier-transform spectrometer for the measurement of high-resolution atmospheric emission spectra at the Earth’s limb. The initial operational products are profiles of temperature, H2O, O3, CH4, N2O, HNO3, and NO2, and this list is extended to include the important GHG (greenhouse gases) and ODS (ozone depleting substances) species using MORSE (orbital retrieval processor). This paper discusses retrievals of minor trace species of HCFC-22, HOCl, OCS, C2H6, COF2, HCN, CF4, SF6, and CCl4. Preliminary zonal mean results of these retrievals are satisfactory except for HCN and CF4 species. We then use MIPAS to estimate the total F and Cl budget in the atmosphere. Comparisons with SLIMCAT are also discussed, with the results consistent. Finally, we focus on improving the retrieval method for minor trace species, COF2, by adjusting correlation length and a priori constraint, as well as the chi-square method introduced to analyze noise. Tests have shown that our improvement could get more information from the measurements

High affinity binding of H3K14ac through collaboration of bromodomains 2, 4 and 5 is critical for the molecular and tumor suppressor functions of PBRM1.

Polybromo-1 (PBRM1) is an important tumor suppressor in kidney cancer. It contains six tandem bromodomains (BDs), which are specialized structures that recognize acetyl-lysine residues. While BD2 has been found to bind acetylated histone H3 lysine 14 (H3K14ac), it is not known whether other BDs collaborate with BD2 to generate strong binding to H3K14ac, and the importance of H3K14ac recognition for the molecular and tumor suppressor function of PBRM1 is also unknown. We discovered that full-length PBRM1, but not its individual BDs, strongly binds H3K14ac. BDs 2, 4, and 5 were found to collaborate to facilitate strong binding to H3K14ac. Quantitative measurement of the interactions between purified BD proteins and H3K14ac or nonacetylated peptides confirmed the tight and specific association of the former. Interestingly, while the structural integrity of BD4 was found to be required for H3K14ac recognition, the conserved acetyl-lysine binding site of BD4 was not. Furthermore, simultaneous point mutations in BDs 2, 4, and 5 prevented recognition of H3K14ac, altered promoter binding and gene expression, and caused PBRM1 to relocalize to the cytoplasm. In contrast, tumor-derived point mutations in BD2 alone lowered PBRM1\u27s affinity to H3K14ac and also disrupted promoter binding and gene expression without altering cellular localization. Finally, overexpression of PBRM1 variants containing point mutations in BDs 2, 4, and 5 or BD2 alone failed to suppress tumor growth in a xenograft model. Taken together, our study demonstrates that BDs 2, 4, and 5 of PBRM1 collaborate to generate high affinity to H3K14ac and tether PBRM1 to chromatin. Mutations in BD2 alone weaken these interactions, and this is sufficient to abolish its molecular and tumor suppressor functions

PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth.

p53 acetylation is indispensable for its transcriptional activity and tumor suppressive function. However, the identity of reader protein(s) for p53 acetylation remains elusive. PBRM1, the second most highly mutated tumor suppressor gene in kidney cancer, encodes PBRM1. Here, we identify PBRM1 as a reader for p53 acetylation on lysine 382 (K382Ac) through its bromodomain 4 (BD4). Notably, mutations on key residues of BD4 disrupt recognition of p53 K382Ac. The mutation in BD4 also reduces p53 binding to promoters of target genes such as CDKN1A (p21). Consequently, the PBRM1 BD4 mutant fails to fully support p53 transcriptional activity and is defective as a tumor suppressor. We also find that expressions of PBRM1 and p21 correlate with each other in human kidney cancer samples. Our findings uncover a tumor suppressive mechanism of PBRM1 in kidney cancer and provide a mechanistic insight into the crosstalk between p53 and SWI/SNF complexes

Cognitive, language, and behavioral outcomes in children with autism spectrum disorders exposed to early comprehensive treatment models: A meta-analysis and meta-regression

Background: Early comprehensive treatment models (CTMs) have been developed as effective treatments for children with autism spectrum disorder (ASD). Numerous studies have suggested that CTMs can improve short-term outcomes, but little is known about precise outcome information in childhood. The current meta-analysis reviewed studies reporting broader outcomes in children with ASD who had ever participated in a CTM and examined the predictors of developmental gains. Methods: We searched eight databases up to June 13, 2019, for relevant trials and natural experiments. Longitudinal studies were selected if they investigated the outcomes of CTMs. Two meta-analyses were undertaken to provide a summary estimate of change in treatment outcomes and to evaluate the effect of CTMs; one used the standardized mean change between the pretest and posttest, and the other was a classical meta-analysis. Stratified and random-effects meta-regression analyses were performed to search for outcome differences among studies. Results: Eighteen intervention studies (involving 495 children with ASD) met all the inclusion criteria: 12 used early intensive behavioral intervention (EIBI), and two used the Early Start Denver Model (ESDM). Outcomes were categorized into three parts: cognitive, language and behavioral (e.g., adaptive functioning and symptomatology). Overall, most children with ASD who had ever participated in an early CTM made gains in many areas of functioning, especially in terms of symptom- and language-related outcomes. Stratified analyses indicated that the ESDM displayed the largest effect on IQ improvement (ES = 1.37, 95% CI: 0.95 to 1.80), while EIBI was more effective for symptom reduction (ES = −1.27, 95% CI: −1.96 to −0.58). Further, meta-regression suggested that interventions with parent involvement, higher intensity, and longer treatment hours yielded greater improvements in IQ and social adaptive functioning, respectively. Conclusion: The results demonstrate a positive association between CTMs and better prognosis in childhood, especially regarding symptoms, and language. However, most extant research involves small, non-randomized studies, preventing definitive conclusions from being drawn. Clearly, the outcomes of children with ASD are still far from normal, especially with respect to adaptive functioning, and the four mediating variables pertaining to treatment elements can affect their gains, including approach, implementer, intensity, and total treatment hours

Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer.

Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/or BAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC. © 2018, Liao et al

Stabilized COre Gene and Pathway Election Uncovers Pan-Cancer Shared Pathways and a Cancer-Specific Driver

Approaches systematically characterizing interactions via transcriptomic data usually follow two systems: (i) coexpression network analyses focusing on correlations between genes and (ii) linear regressions (usually regularized) to select multiple genes jointly. Both suffer from the problem of stability: A slight change of parameterization or dataset could lead to marked alterations of outcomes. Here, we propose Stabilized COre gene and Pathway Election (SCOPE), a tool integrating bootstrapped least absolute shrinkage and selection operator and coexpression analysis, leading to robust outcomes insensitive to variations in data. By applying SCOPE to six cancer expression datasets (BRCA, COAD, KIRC, LUAD, PRAD, and THCA) in The Cancer Genome Atlas, we identified core genes capturing interaction effects in crucial pan-cancer pathways related to genome instability and DNA damage response. Moreover, we highlighted the pivotal role of CD63 as an oncogenic driver and a potential therapeutic target in kidney cancer. SCOPE enables stabilized investigations toward complex interactions using transcriptome data