Publications by authors named "Chenghua Yang"

26 Publications

  • Page 1 of 1

TAGLN Is Downregulated by TRAF6-Mediated Proteasomal Degradation in Prostate Cancer Cells.

Mol Cancer Res 2021 Mar 26. Epub 2021 Mar 26.

Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China.

Transgelin (TAGLN, also named SM22) is an actin-associated protein and affects dynamics of actin filaments. Deregulation of TAGLN contributes to the development of different cancers, and it is commonly considered to be a tumor suppressor. TAGLN is usually downregulated in prostate cancer; however, the detailed functions of TAGLN in prostate cancer and how TAGLN is regulated remains unclear. In this study, we confirmed that TAGLN is downregulated in prostate cancer tissues and demonstrated that the downregulation of TAGLN occurs through proteasomal degradation. Next, we found that the expression level of TAGLN is inversely correlated with TRAF6. We screened more than 20 E2-E3 pairs by ubiquitination assay and found that the E2A-TRAF6 pair catalyzed mono ubiquitination of TAGLN. We then identified the ubiquitination sites of TAGLN to be on K89 or K108 residues and demonstrated that ubiquitination of TAGLN on K89/K108 are important for TRAF6-mediated proteasomal degradation. Furthermore, we investigated the function of TAGLN in prostate cancer cells. We found that ablation of TAGLN promoted prostate cancer cell proliferation and suppressed their migration via activation of NF-κB and Myc signaling pathways. Overall, our study provided new insights into the mechanisms underlying TAGLN expression and activity in prostate cancer. IMPLICATIONS: E3 ligase TRAF6 mediate mono-ubiquitination and degradation of TAGLN, which leads to activation of NF-κB and Myc signaling pathways in prostate cancer cells.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0513DOI Listing
March 2021

MALT1 as a promising target to treat lymphoma and other diseases related to MALT1 anomalies.

Med Res Rev 2021 Mar 25. Epub 2021 Mar 25.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key adaptor protein that regulates the NF-κB pathway, in which MALT1 functions as a scaffold protein and protease to trigger downstream signals. The abnormal expression of MALT1 is closely associated with lymphomagenesis and other diseases, including solid tumors and autoimmune diseases. MALT1 is the only protease in the underlying pathogenesis of these diseases, and its proteolytic activity can be pharmacologically regulated. Therefore, MALT1 is a potential and promising target for anti-lymphoma and other MALT1-related disease treatments. Currently, the development of MALT1 inhibitors is still in its early stages. This review presents an overview of MALT1, particularly its X-ray structures and biological functions, and elaborates on the pathogenesis of diseases associated with its dysregulation. We then summarize previously reported MALT1 inhibitors, focusing on their molecular structure, biological activity, structure-activity relationship, and limitations. Finally, we propose future research directions to accelerate the discovery of novel MALT1 inhibitors with clinical applications. Overall, this review provides a comprehensive and systematic overview of MALT1-related research advances and serves as a theoretical basis for drug discovery and research.
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http://dx.doi.org/10.1002/med.21799DOI Listing
March 2021

Targeting BCL10 by small peptides for the treatment of B cell lymphoma.

Theranostics 2020 19;10(25):11622-11636. Epub 2020 Sep 19.

Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China, 200433.

Constitutive activation of the NF-κB signalling pathway plays a pivotal role in the pathogenesis of activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCLs), the most aggressive and chemoresistant form of DLBCL. In ABC-DLBCLs, the CARMA1-BCL10 (CB) complex forms a filamentous structure and functions as a supramolecular organizing centre (CB-SMOC) that is required for constitutive NF-κB activation, making it an attractive drug target for ABC-DLBCL treatment. However, a pharmaceutical approach targeting CB-SMOC has been lacking. Here, we developed Bcl10 peptide inhibitors (BPIs) that specifically target the BCL10 filamentation process. Electron microscopy and immunofluorescence imaging were used to visualize the effect of the BPIs on the BCL10 filamentation process. The cytotoxicity of the tested BPIs was evaluated in DLBCL cell lines according to cell proliferation assays. Different experiments (pharmacokinetics, immunoprecipitation, western blotting, annexin V and PI staining) were conducted to determine the functional mechanisms of the BPIs. The therapeutic effect of the BPIs was examined in different xenograft DLBCL mouse models. Finally, Ki67 and TUNEL staining and histopathology analysis were used to evaluate the antineoplastic mechanisms and systemic toxicity of the BPIs. We showed that these BPIs can effectively disrupt the BCL10 filamentation process, destabilize BCL10 and suppress NF-κB signalling in ABC-DLBCL cells. By examining a panel of DLBCL cell lines, we found that these BPIs selectively repressed the growth of CB-SMOC-dependent DLBCL cells by inducing apoptosis and cell cycle arrest. Moreover, by converting the BPIs to acquire a D-retro inverso (DRI) configuration, we developed DRI-BPIs with significantly improved intracellular stability and unimpaired BPI activity. These DRI-BPIs selectively repressed the growth of CB-SMOC-dependent DLBCL tumors in mouse xenograft models without eliciting discernible adverse effects. We developed novel BPIs to target the BCL10 filamentation process and demonstrated that targeting BCL10 by BPIs is a potentially safe and effective pharmaceutical approach for the treatment of ABC-DLBCL and other CB-SMOC-dependent malignancies.
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http://dx.doi.org/10.7150/thno.47533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546004PMC
September 2020

Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone.

Cell Rep 2020 06;31(13):107840

Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Stresses associated with disease may pathologically remodel the proteome by both increasing interaction strength and altering interaction partners, resulting in proteome-wide connectivity dysfunctions. Chaperones play an important role in these alterations, but how these changes are executed remains largely unknown. Our study unveils a specific N-glycosylation pattern used by a chaperone, Glucose-regulated protein 94 (GRP94), to alter its conformational fitness and stabilize a state most permissive for stable interactions with proteins at the plasma membrane. This "protein assembly mutation' remodels protein networks and properties of the cell. We show in cells, human specimens, and mouse xenografts that proteome connectivity is restorable by inhibition of the N-glycosylated GRP94 variant. In summary, we provide biochemical evidence for stressor-induced chaperone-mediated protein mis-assemblies and demonstrate how these alterations are actionable in disease.
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http://dx.doi.org/10.1016/j.celrep.2020.107840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372946PMC
June 2020

A genomic and epigenomic atlas of prostate cancer in Asian populations.

Nature 2020 04 25;580(7801):93-99. Epub 2020 Mar 25.

Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China.

Prostate cancer is the second most common cancer in men worldwide. Over the past decade, large-scale integrative genomics efforts have enhanced our understanding of this disease by characterizing its genetic and epigenetic landscape in thousands of patients. However, most tumours profiled in these studies were obtained from patients from Western populations. Here we produced and analysed whole-genome, whole-transcriptome and DNA methylation data for 208 pairs of tumour tissue samples and matched healthy control tissue from Chinese patients with primary prostate cancer. Systematic comparison with published data from 2,554 prostate tumours revealed that the genomic alteration signatures in Chinese patients were markedly distinct from those of Western cohorts: specifically, 41% of tumours contained mutations in FOXA1 and 18% each had deletions in ZNF292 and CHD1. Alterations of the genome and epigenome were correlated and were predictive of disease phenotype and progression. Coding and noncoding mutations, as well as epimutations, converged on pathways that are important for prostate cancer, providing insights into this devastating disease. These discoveries underscore the importance of including population context in constructing comprehensive genomic maps for disease.
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http://dx.doi.org/10.1038/s41586-020-2135-xDOI Listing
April 2020

Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib.

J Immunother Cancer 2020 03;8(1)

State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Background: There is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Immunotherapy is promising especially when combined with traditional therapies. This study aimed to investigate the immunomodulatory function of an approved Chinese medicine formula, compound kushen injection (CKI), and its anti-HCC efficiency in combination with low-dose sorafenib.

Methods: Growth of two murine HCC cells was evaluated in an orthotopic model, a subcutaneous model, two postsurgical recurrence model, and a tumor rechallenge model with CKI and low-dose sorafenib combination treatment. In vivo macrophage or CD8 T cell depletion and in vitro primary cell coculture models were used to determine the regulation of CKI on macrophages and CD8 T cells.

Results: CKI significantly enhanced the anticancer activity of sorafenib at a subclinical dose with no obvious side effects. CKI and sorafenib combination treatment prevented the postsurgical recurrence and rechallenged tumor growth. Further, we showed that CKI activated proinflammatory responses and relieved immunosuppression of tumor-associated macrophages in the HCC microenvironment by triggering tumor necrosis factor receptor superfamily member 1 (TNFR1)-mediated NF-κB and p38 MAPK signaling cascades. CKI-primed macrophages significantly promoted the proliferation and the cytotoxic ability of CD8 T cells and decreased the exhaustion, which subsequently resulted in apoptosis of HCC cells.

Conclusions: CKI acts on macrophages and CD8 T cells to reshape the immune microenvironment of HCC, which improves the therapeutic outcomes of low-dose sorafenib and avoids adverse chemotherapy effects. Our study shows that traditional Chinese medicines with immunomodulatory properties can potentiate chemotherapeutic drugs and provide a promising approach for HCC treatment.
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http://dx.doi.org/10.1136/jitc-2019-000317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073790PMC
March 2020

Recognition of Invasive Prostate Cancer Using a GHRL Polypeptide Probe Targeting GHSR in a Mouse Model .

Curr Pharm Des 2020 ;26(14):1614-1621

Department of Urology, Shanghai Changhai Hospital Affiliated to the Second Military Medical University, Shanghai, China.

Background: Ghrelin (GHRL) is a polypeptide that can specifically bind to the growth hormone secretagogue receptor (GHSR). The expression of GHSR is significantly different in normal and prostate cancer (PC) tissues in humans. It is important to find an effective diagnostic method for the diagnosis and prognosis of invasive PC/neuroendocrine prostate cancer (NEPC).

Methods: GHRL and GHSR mRNA levels were determined by a quantitative real-time polymerase chain reaction in PC tissues. The expression of GHRL and GHSR proteins was assessed by Western blot assay and immunohistochemistry. A GHRL polypeptide probe was synthesized by standard solid-phase polypeptide synthesis, and labeled with Alexa Fluor 660. Confocal microscopy was used to capture fluorescence images. Living imaging analysis showed tumor areas of different invasiveness in mice models.

Results: The levels of GHRL and GHSR copy number amplification and mRNA expression were increased in invasive PC/NEPC, and the protein expression levels of GHRL and GHSR were similarly increased in NEPC. The GHRL polypeptide probe could effectively bind to GHSR. In PC3 cells, it was found that the GHRL probe specifically binds to GHSR on the cell membrane and accumulates in the cells through internalization after binding. Live imaging in mice models showed that there were different signal intensities in tumor areas with different invasiveness.

Conclusion: GHSR and GHRL might be used in molecular imaging diagnosis for invasive PC/NEPC in the future.
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http://dx.doi.org/10.2174/1381612826666191227160001DOI Listing
November 2020

Setting off firecrackers: An economic way to release inner stress for patients with depression.

Perspect Psychiatr Care 2019 Jul 17;55(3):372. Epub 2018 Jul 17.

Medical Science and Technology Department, Fengxian Hospital, Southern Medical University, Shanghai, China.

Purpose: To advocate an economic way to release inner stress for patients with depression.

Conclusions: Setting off firecrackers has psychological value. It is not merely for fun, but is more an economic and easy behavioral therapy in psychiatric care, even risking a little bit noise and air pollution, especially for patients with depression.

Practice Implications: In routine psychiatric care practice, patient with depression were encouraged to set off firecrackers to release their stress.
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http://dx.doi.org/10.1111/ppc.12310DOI Listing
July 2019

Alterations in expressed prostate secretion-urine PSA N-glycosylation discriminate prostate cancer from benign prostate hyperplasia.

Oncotarget 2017 Sep 16;8(44):76987-76999. Epub 2017 Aug 16.

Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 2000433, China.

The prostate specific antigen (PSA) test is widely used for early diagnosis of prostate cancer (PCa). However, its limited sensitivity has led to over-diagnosis and over-treatment of PCa. Glycosylation alteration is a common phenomenon in cancer development. Different PSA glycan subforms have been proposed as diagnostic markers to better differentiate PCa from benign prostate hyperplasia (BPH). In this study, we purified PSA from expressed prostate secretions (EPS)-urine samples from 32 BPH and 30 PCa patients and provided detailed PSA glycan profiles in Chinese population. We found that most of the PSA glycans from EPS-urine were complex type biantennary glycans. We observed two major patterns in PSA glycan profiles. Overall there was no distinct separation of PSA glycan profiles between BPH and PCa patients. However, we detected a significant increase of glycan FA2 and FM5A2G2S1 in PCa when compared with BPH patients. Furthermore, we observed that the composition of FA2 glycan increased significantly in advanced PCa with Gleason score ≥8, which potentially could be translated to clinic as a marker for aggressive PCa.
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http://dx.doi.org/10.18632/oncotarget.20299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652757PMC
September 2017

Signal restoration method for restraining the range walk error of Geiger-mode avalanche photodiode lidar in acquiring a merged three-dimensional image.

Appl Opt 2017 Apr;56(11):3059-3063

The fluctuation in the number of signal photoelectrons will cause a range walk error in a Geiger-mode avalanche photodiode (Gm-APD) lidar, which significantly depends on the target intensity. For a nanosecond-pulsed laser, the range walk error of traditional time-of-flight will cause deterioration. A new signal restoration method, based on the Poisson probability response model and the center-of-mass algorithm, is proposed to restrain the range walk error. We obtain a high-precision depth and intensity merged 3D image using this method. The range accuracy is 0.6 cm, and the intensity error is less than 3%.
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http://dx.doi.org/10.1364/AO.56.003059DOI Listing
April 2017

The epichaperome is an integrated chaperome network that facilitates tumour survival.

Nature 2016 Oct 5;538(7625):397-401. Epub 2016 Oct 5.

Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.
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http://dx.doi.org/10.1038/nature19807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283383PMC
October 2016

PAQR3 suppresses the proliferation, migration and tumorigenicity of human prostate cancer cells.

Oncotarget 2017 Aug 3;8(33):53948-53958. Epub 2016 Jun 3.

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.

As a newly discovered tumor suppressor, the potential function of PAQR3 in human prostate cancer has not been demonstrated. In this study, we report that PAQR3 is able to inhibit the growth and migration of human prostate cancer cells both and . Overexpression of PAQR3 inhibits the proliferation of PC3 and DU145 cells by both MTT and colony formation assays. Consistently, knockdown of PAQR3 enhances the proliferation of these cells. In wound-healing and transwell assays, overexpression of PAQR3 reduces the migration of PC3 and DU145 cells, while PAQR3 knockdown increases it. In a tumor xenograft model, overexpression of PAQR3 suppresses tumor growth of PC3 cells , while PAQR3 knockdown promotes the tumor growth. PAQR3 is also able to inhibit serum-induced phosphorylation of AKT and ERK in both PC3 and DU145 cells. In addition, PAQR3 suppresses the expression of epithelial-mesenchymal transition (EMT) markers in PC3 cells. Collectively, these data indicate that PAQR3 has a tumor suppressive activity in human prostate cancer cells and may stand out as a potential therapeutic target for prostate cancers.
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http://dx.doi.org/10.18632/oncotarget.9807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589553PMC
August 2017

Restraint of range walk error in a Geiger-mode avalanche photodiode lidar to acquire high-precision depth and intensity information.

Appl Opt 2016 Mar;55(7):1683-7

There exists a range walk error in a Geiger-mode avalanche photodiode (Gm-APD) lidar because of the fluctuation in the number of signal photoelectrons. To restrain this range walk error, we propose a new returning-wave signal processing technique based on the Poisson probability response model and the Gaussian functions fitting method. High-precision depth and intensity information of the target at the distance of 5 m is obtained by a Gm-APD lidar using a 6 ns wide pulsed laser. The experiment results show that the range and intensity precisions are 1.2 cm and 0.015 photoelectrons, respectively.
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http://dx.doi.org/10.1364/AO.55.001683DOI Listing
March 2016

Super-resolving quantum lidar: entangled coherent-state sources with binary-outcome photon counting measurement suffice to beat the shot-noise limit.

Opt Express 2016 Mar;24(5):5045-5056

We investigate the performance of the super-resolving quantum lidar with the entangled coherent states of light in the presence of loss and noise, especially in the noisy case. An exact analytical expression of the output signal has been derived with the binary-outcome photon counting measurements. Numerical results show that the resolution of our scheme with parity detection is √N (N) times enhanced relative to that of the coherent-state strategy with the same (intensity) detection in the lossless and noiseless cases. The influences of phase diffusion on resolution and sensitivity have been analyzed and discussed. It is found that the super-resolution emerges in the whole diffusion rate regions, whereas the super-sensitivity just exists in the high and low diffusion rate regimes. Comparisons are made with the well known N00N states, the results show that the entangled coherent states performs better resolution and sensitivity than those of the N00N scheme in the whole diffusion regimes. In addition, the effects of photon loss on resolution and sensitivity have also been studied. The phase sensitivity can beat the shot noise limit and the resolution is much better than the Rayleigh diffraction limit in the whole loss regions. Finally, the zero-nonzero photon counting measurement gives much worse sensitivity than that of the parity detection, which is just opposite from the case as demonstrated in a recent coherent-light Mach-Zehnder experiment.
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http://dx.doi.org/10.1364/OE.24.005045DOI Listing
March 2016

Affinity purification probes of potential use to investigate the endogenous Hsp70 interactome in cancer.

ACS Chem Biol 2014 Aug 17;9(8):1698-705. Epub 2014 Jun 17.

Program in Molecular Pharmacology and Chemistry and Department of Medicine and §Program in Molecular Biology, Proteomics Core, Memorial Sloan-Kettering Cancer Center , New York, New York 10021, United States.

Heat shock protein 70 (Hsp70) is a family of proteins with key roles in regulating malignancy. Cancer cells rely on Hsp70 to inhibit apoptosis, regulate senescence and autophagy, and maintain the stability of numerous onco-proteins. Despite these important biological functions in cancer, robust chemical tools that enable the analysis of the Hsp70-regulated proteome in a tumor-by-tumor manner are yet unavailable. Here we take advantage of a recently reported Hsp70 ligand to design and develop an affinity purification chemical toolset for potential use in the investigation of the endogenous Hsp70-interacting proteome in cancer. We demonstrate that these tools lock Hsp70 in complex with onco-client proteins and effectively isolate Hsp70 complexes for identification through biochemical techniques. Using these tools we provide proof-of-concept analyses that glimpse into the complex roles played by Hsp70 in maintaining a multitude of cell-specific malignancy-driving proteins.
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http://dx.doi.org/10.1021/cb500256uDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134716PMC
August 2014

De novo formation of insulin-producing "neo-β cell islets" from intestinal crypts.

Cell Rep 2014 Mar 6;6(6):1046-1058. Epub 2014 Mar 6.

Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

The ability to interconvert terminally differentiated cells could serve as a powerful tool for cell-based treatment of degenerative diseases, including diabetes mellitus. To determine which, if any, adult tissues are competent to activate an islet β cell program, we performed an in vivo screen by expressing three β cell "reprogramming factors" in a wide spectrum of tissues. We report that transient intestinal expression of these factors-Pdx1, MafA, and Ngn3 (PMN)-promotes rapid conversion of intestinal crypt cells into endocrine cells, which coalesce into "neoislets" below the crypt base. Neoislet cells express insulin and show ultrastructural features of β cells. Importantly, intestinal neoislets are glucose-responsive and able to ameliorate hyperglycemia in diabetic mice. Moreover, PMN expression in human intestinal "organoids" stimulates the conversion of intestinal epithelial cells into β-like cells. Our results thus demonstrate that the intestine is an accessible and abundant source of functional insulin-producing cells.
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http://dx.doi.org/10.1016/j.celrep.2014.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245054PMC
March 2014

Synthesis of copolymers with cyclodextrin as pendants and its end group effect as superplasticizer.

Carbohydr Polym 2014 Feb 4;102:278-87. Epub 2013 Dec 4.

Key Laboratory of Polymer Materials for Electronics, Guangzhou Institute of Chemistry, Chinese Academy of Sciences, Guangzhou 510650, PR China. Electronic address:

In this paper, the efficient approach for the synthesis of β-cyclodextrin (CD) based functional monomers was described. Based on the monovinyl β-CD monomer (GMA-EDA-CD), a new type poly(AA-co-GMA-EDA-CD) (PCDs) copolymer bearing pendent CD groups was synthesized and used as superplasticizer. Their chemical compositions were characterized by FT-IR, NMR, MALDI-TOF and GPC. The effects of PCDs on dispersion and adsorption in cement mortars were detailed discussed. The results indicated that PCD copolymers behaved excellent dispersion ability and strong retarding effect. PCD2 with molar ratio (%) for monomer (AA:GMA-EDA-CD=80:20) had the best dispersion and dispersion maintaining abilities, which were mainly attributed to the synergistic effects of steric hindrance and electrostatic repulsive force, and the retarding effect of PCD copolymers resulted from steric hindrance repulsion of CD pendants and the large number of hydroxyl groups, which affected the hydration reaction of cement.
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http://dx.doi.org/10.1016/j.carbpol.2013.11.044DOI Listing
February 2014

Pdx1 maintains β cell identity and function by repressing an α cell program.

Cell Metab 2014 Feb;19(2):259-71

Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Pdx1 is a homeobox-containing transcription factor that plays a key role in pancreatic development and adult β cell function. In this study, we traced the fate of adult β cells after Pdx1 deletion. As expected, β-cell-specific removal of Pdx1 resulted in severe hyperglycemia within days. Surprisingly, a large fraction of Pdx1-deleted cells rapidly acquired ultrastructural and physiological features of α cells, indicating that a robust cellular reprogramming had occurred. Reprogrammed cells exhibited a global transcriptional shift that included derepression of the α cell transcription factor MafB, resulting in a transcriptional profile that closely resembled that of α cells. These findings indicate that Pdx1 acts as a master regulator of β cell fate by simultaneously activating genes essential for β cell identity and repressing those associated with α cell identity. We discuss the significance of these findings in the context of the emerging notion that loss of β cell identity contributes to the pathogenesis of type 2 diabetes.
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http://dx.doi.org/10.1016/j.cmet.2013.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950964PMC
February 2014

The CBM signalosome: potential therapeutic target for aggressive lymphoma?

Cytokine Growth Factor Rev 2014 Apr 24;25(2):175-83. Epub 2013 Dec 24.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.

The CBM signalosome plays a pivotal role in mediating antigen-receptor induced NF-κB signaling to regulate lymphocyte functions. The CBM complex forms filamentous structure and recruits downstream signaling components to activate NF-κB. MALT1, the protease component in the CBM complex, cleaves key proteins in the feedback loop of the NF-κB signaling pathway and enhances NF-κB activation. The aberrant activity of the CBM complex has been linked to aggressive lymphoma. Recent years have witnessed dramatic progresses in understanding the assembly mechanism of the CBM complex, and advances in the development of targeted therapy for aggressive lymphoma. Here, we will highlight these progresses and give an outlook on the potential translation of this knowledge from bench to bedside for aggressive lymphoma patients.
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http://dx.doi.org/10.1016/j.cytogfr.2013.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080217PMC
April 2014

Identification of an allosteric pocket on human hsp70 reveals a mode of inhibition of this therapeutically important protein.

Chem Biol 2013 Dec 14;20(12):1469-80. Epub 2013 Nov 14.

Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. Electronic address:

Hsp70s are important cancer chaperones that act upstream of Hsp90 and exhibit independent anti-apoptotic activities. To develop chemical tools for the study of human Hsp70, we developed a homology model that unveils a previously unknown allosteric site located in the nucleotide binding domain of Hsp70. Combining structure-based design and phenotypic testing, we discovered a previously unknown inhibitor of this site, YK5. In cancer cells, this compound is a potent and selective binder of the cytosolic but not the organellar human Hsp70s and has biological activity partly by interfering with the formation of active oncogenic Hsp70/Hsp90/client protein complexes. YK5 is a small molecule inhibitor rationally designed to interact with an allosteric pocket of Hsp70 and represents a previously unknown chemical tool to investigate cellular mechanisms associated with Hsp70.
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http://dx.doi.org/10.1016/j.chembiol.2013.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985611PMC
December 2013

Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly.

Mol Cell 2013 Sep;51(6):766-79

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.

The CARMA1/Bcl10/MALT1 (CBM) signalosome mediates antigen receptor-induced NF-κB signaling to regulate multiple lymphocyte functions. While CARMA1 and Bcl10 contain caspase recruitment domains (CARDs), MALT1 is a paracaspase with structural similarity to caspases. Here we show that the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments. Bcl10 filament formation is a highly cooperative process whose threshold is sensitized by oligomerized CARMA1 upon receptor activation. In cells, both cotransfected CARMA1/Bcl10 complex and the endogenous CBM signalosome are filamentous morphologically. Combining crystallography, nuclear magnetic resonance, and electron microscopy, we reveal the structure of the Bcl10 CARD filament and the mode of interaction between CARMA1 and Bcl10. Structure-guided mutagenesis confirmed the observed interfaces in Bcl10 filament assembly and MALT1 activation in vitro and NF-κB activation in cells. These data support a paradigm of nucleation-induced signal transduction with threshold response due to cooperativity and signal amplification by polymerization.
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http://dx.doi.org/10.1016/j.molcel.2013.08.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929958PMC
September 2013

Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2.

Nat Chem Biol 2013 Nov 1;9(11):677-84. Epub 2013 Sep 1.

1] Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York, USA. [2] Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA. [3].

Although the Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90α, Hsp90β, Grp94 and Trap-1, has important roles in malignancy, the contribution of each paralog to the cancer phenotype is poorly understood. This is in large part because reagents to study paralog-specific functions in cancer cells have been unavailable. Here we combine compound library screening with structural and computational analyses to identify purine-based chemical tools that are specific for Hsp90 paralogs. We show that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket. We use these tools to demonstrate that cancer cells use individual Hsp90 paralogs to regulate a client protein in a tumor-specific manner and in response to proteome alterations. Finally, we provide new mechanistic evidence explaining why selective Grp94 inhibition is particularly efficacious in certain breast cancers.
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http://dx.doi.org/10.1038/nchembio.1335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982621PMC
November 2013

Hippo signaling regulates differentiation and maintenance in the exocrine pancreas.

Gastroenterology 2013 Jun 27;144(7):1543-53, 1553.e1. Epub 2013 Feb 27.

Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Background & Aims: The Hippo signaling pathway is a context-dependent regulator of cell proliferation, differentiation, and apoptosis in species ranging from Drosophila to humans. In this study, we investigated the role of the core Hippo kinases-Mst1 and Mst2-in pancreatic development and homeostasis.

Methods: We used a Cre/LoxP system to create mice with pancreas-specific disruptions in Mst1 and Mst2 (Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice), the mammalian orthologs of Drosophila Hippo. We used a transgenic approach to overexpress Yap, the downstream mediator of Hippo signaling, in the developing pancreas of mice.

Results: Contrary to expectations, the pancreatic mass of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice was reduced compared with wild-type mice, largely because of postnatal de-differentiation of acinar cells into duct-like cells. Development of this phenotype coincided with postnatal reactivation of YAP expression. Ectopic expression of YAP during the secondary transition (a stage at which YAP is normally absent) blocked differentiation of the endocrine and exocrine compartments, whereas loss of a single Yap allele reduced acinar de-differentiation. The phenotype of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice recapitulated cellular and molecular changes observed during chemical-induced pancreatitis in mice.

Conclusions: The mammalian Hippo kinases, and YAP, maintain postnatal pancreatic acinar differentiation in mice.
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http://dx.doi.org/10.1053/j.gastro.2013.02.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665616PMC
June 2013

MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo.

Cancer Cell 2012 Dec;22(6):812-24

Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY 10021, USA.

MALT1 cleavage activity is linked to the pathogenesis of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), a chemoresistant form of DLBCL. We developed a MALT1 activity assay and identified chemically diverse MALT1 inhibitors. A selected lead compound, MI-2, featured direct binding to MALT1 and suppression of its protease function. MI-2 concentrated within human ABC-DLBCL cells and irreversibly inhibited cleavage of MALT1 substrates. This was accompanied by NF-κB reporter activity suppression, c-REL nuclear localization inhibition, and NF-κB target gene downregulation. Most notably, MI-2 was nontoxic to mice, and displayed selective activity against ABC-DLBCL cell lines in vitro and xenotransplanted ABC-DLBCL tumors in vivo. The compound was also effective against primary human non-germinal center B cell-like DLBCLs ex vivo.
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http://dx.doi.org/10.1016/j.ccr.2012.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984478PMC
December 2012

Biophysical analysis and small-angle X-ray scattering-derived structures of MeCP2-nucleosome complexes.

Nucleic Acids Res 2011 May 29;39(10):4122-35. Epub 2011 Jan 29.

Department of Biochemistry and Molecular Biology and Howard Hughes Medical Institute, Colorado State University, Fort Collins, CO 80523-1870, USA.

MeCP2 is a highly abundant chromatin architectural protein with key roles in post-natal brain development in humans. Mutations in MeCP2 are associated with Rett syndrome, the main cause of mental retardation in girls. Structural information on the intrinsically disordered MeCP2 protein is restricted to the methyl-CpG binding domain; however, at least four regions capable of DNA and chromatin binding are distributed over its entire length. Here we use small angle X-ray scattering (SAXS) and other solution-state approaches to investigate the interaction of MeCP2 and a truncated, disease-causing version of MeCP2 with nucleosomes. We demonstrate that MeCP2 forms defined complexes with nucleosomes, in which all four histones are present. MeCP2 retains an extended conformation when binding nucleosomes without extra-nucleosomal DNA. In contrast, nucleosomes with extra-nucleosomal DNA engage additional DNA binding sites in MeCP2, resulting in a rather compact higher-order complex. We present ab initio envelope reconstructions of nucleosomes and their complexes with MeCP2 from SAXS data. SAXS studies also revealed unexpected sequence-dependent conformational variability in the nucleosomes themselves.
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http://dx.doi.org/10.1093/nar/gkr005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105411PMC
May 2011

Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response.

J Clin Invest 2006 May 20;116(5):1243-53. Epub 2006 Apr 20.

National Human Genome Research Institute, National Eye Institute, and National Institute of Child Health and Development, NIH, Bethesda, Maryland 20892, USA.

Inflammatory skin disorders result in significant epidermal changes, including keratinocyte hyperproliferation, incomplete differentiation, and impaired barrier. Here we test whether, conversely, an impaired epidermal barrier can promote an inflammatory response. Mice lacking the transcription factor Kruppel-like factor 4 (Klf4) have a severe defect in epidermal barrier acquisition. Transcription profiling of Klf4(-/-) newborn skin revealed similar changes in gene expression to involved psoriatic plaques, including a significant upregulation of the gap junction protein connexin 26 (Cx26). Ectopic expression of Cx26 from the epidermis-specific involucrin (INV) promoter (INV-Cx26) demonstrated that downregulation of Cx26 is required for barrier acquisition during development. In juvenile and adult mice, persistent Cx26 expression kept wounded epidermis in a hyperproliferative state, blocked the transition to remodeling, and led to an infiltration of immune cells. Mechanistically, ectopic expression of Cx26 in keratinocytes resulted in increased ATP release, which delayed epidermal barrier recovery and promoted an inflammatory response in resident immune cells. These results provide a molecular link between barrier acquisition in utero and epidermal remodeling after wounding. More generally, these studies suggest that the most effective treatments for inflammatory skin disorders might concomitantly suppress the immune response and enhance epidermal differentiation to restore the barrier.
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http://dx.doi.org/10.1172/JCI27186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1440704PMC
May 2006