Biomedical subjects

Nan Li

Publications and source records attributed to Nan Li.

At least 19 recordsLinked to original sources

PubMed2026

Driver genomic lesions in MDM2, CDK4, and JUN co-opt targetable super-enhancer networks to impose liposarcomagenic core regulatory circuitry.

INTRODUCTION: Amplification of chromosome 12q13-15 spanning MDM2 and CDK4 genes serves as a molecular diagnostic hallmark of dedifferentiated liposarcoma (DDLPS), an aggressive soft-tissue sarcoma. Epigenetic activation of master transcription factors (RUNX proteins, FOSL2, and MYC) establishes a self-reinforcing oncogenic transcriptional circuitry in DDLPS. Nevertheless, the collaborative interplay between genomic alterations and epigenetic dysregulation in defining DDLPS cell identity remains elusive. OBJECTIVES: This work aimed to elucidate the primary genetic drivers and mechanistic basis of DDLPS-specific core transcriptional regulatory circuitry. METHODS: We performed integrative chromatin profiling analysis of DDLPS clinical specimens and cell lines to map cis-regulatory landscapes. Cistromes of MDM2, JUN, and E2F1 were delineated through chromatin immunoprecipitation sequencing in two DDLPS models. Essential driver functions and transcriptional regulatory effects of key regulators were assessed via various genetic manipulation approaches. Synergistic interactions between BET-targeting agents and MDM2/p53 or CDK4 inhibitors were quantified by cell viability assays. In vivo xenograft assays evaluated the oncogenic potential of key regulators and the therapeutic efficacy of novel strategies. RESULTS: Co-amplification of MDM2, CDK4, and JUN during sarcomagenesis converges with BET protein-dependent chromatin remodeling to fuel feed-forward transcriptional circuits among master transcription factors. Mechanistically, excessively expressed MDM2 stabilizes the core regulatory circuitry by forming chromatin-bound complexes with JUN/FOSL2 at cis-regulatory elements, especially super-enhancers across DDLPS genome. Concurrently, CDK4 maintains expression of E2F1 which further fosters transcriptional output of master transcription factors in DDLPS cells. Leveraging DDLPS-selective overexpression of MDM2 and its E3 ligase activity, targeted degradation of BET proteins by MDM2-recruiting proteolysis targeting chimera selectively disrupted the core regulatory circuitry, suppressing DDLPS growth and exhibiting strong synergy with CDK4 inhibitor. CONCLUSION: DDLPS-associated genomic lesions collaborate with BET-dependent chromatin regulation to establish disease-sustaining transcriptional circuitry. Our findings also provide a mechanistic rationale for harnessing MDM2's E3 ligase activity to therapeutically degrade oncoproteins in MDM2-amplified malignancies.

Core transcriptional regulatory circuitry↗

PubMed2026

AI proteomics: from protein identification to virtual cells.

Artificial intelligence (AI) is transforming scientific research, including proteomics. In this Perspective, we highlight key mass spectrometry (MS)-based proteomics areas where AI is driving innovation, ranging from protein identification to building AI virtual cells. These include improving peptide and protein identification and quantification; characterizing protein-protein interactions and protein complexes; advancing spatial and perturbation proteomics; integrating multi-omics data; and, ultimately, enabling AI virtual cells. Finally, we call for global collaboration among data producers, data consumers and other stakeholders to establish an AI-friendly ecosystem for MS-based proteomics, laying the foundation for transformative advancements in proteomics driven by AI.

Proteomics↗

PubMed2007

Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate.

Numerous microRNAs (miRNAs) have been discovered in the genomes of higher eukaryotes, and functional studies indicate that they are important during development. However, little is known concerning the function of individual miRNAs. We approached this problem in zebrafish by combining identification of miRNA expression, functional analyses and experimental validation of potential targets. We show that miR-214 is expressed during early segmentation stages in somites and that varying its expression alters the expression of genes regulated by Hedgehog signaling. Inhibition of miR-214 results in a reduction or loss of slow-muscle cell types. We show that su(fu) mRNA, encoding a negative regulator of Hedgehog signaling, is targeted by miR-214. Through regulation of su(fu), miR-214 enables precise specification of muscle cell types by sharpening cellular responses to Hedgehog.

Animals↗

PubMed2007

Pathophysiology of glutamine and glutamate metabolism in premature infants.

PURPOSE OF REVIEW: The potential efficacy of glutamine and glutamate as nutritional supplements for premature infants was originally met with enthusiasm. Despite no evidence of toxicity in the clinical trials, the use of glutamine has not become routine. In certain studies, the benefits seem clear, whereas in others, benefits have not been demonstrated. Specific designs for studies have been difficult, targets based on mechanistic frameworks have been poorly defined, study populations are heterogeneous and putative mechanisms of glutamine action are multifold. Our purpose is to review recent findings pertaining to (1) the action and mechanisms of glutamine and glutamate in the gastrointestinal tract, and (2) the future directions for glutamine and glutamate research with a focus on the premature neonate. RECENT FINDINGS: Studies elucidating mechanisms of glutamine action include tissue protection, immune modulation, preservation of glutathione and antioxidant capacity, preservation of metabolism, decreased intestinal apoptosis, and enhancement of heat shock proteins. The ability to decrease gastrointestinal-derived systemic inflammation appears to have especially significant implications for premature infants. SUMMARY: We review recent studies of mechanisms of glutamine and glutamate action, pertinent clinical trials, and suggest areas for future research based on these mechanisms.

Bacterial Translocation↗

PubMed2007

Promotion of cellular migration and apoptosis resistance by a mouse eye-specific phosphatidylethanolamine-binding protein.

The phosphatidylethanolamine (PE)-binding protein (PEBP) family is an evolutionary conserved group of proteins found in various species with multiple functions. We identified human PE-binding protein 4 (hPEBP4), a novel member of the PEBP family, as an anti-apoptotic molecule. Here we describe the cloning and functional characterization of the mouse homolog of hPEBP4 (mouse PEBP4, mPEBP4). Full-length cDNA of mPEBP4 contains 1048 bp with an open reading frame (ORF) of 729 bp, which is predicted to encode a 242-aa protein. mPEBP4 contains a PE-binding domain, in this case between amino acids 106 and 213. mPEBP4 localizes primarily to endoplasmic reticulum/Golgi apparatus. Interestingly, RT-PCR and in situ hybridization analyses indicate that mPEBP4 is specifically expressed in mouse eye tissue. We demonstrate that mPEBP4 promotes cellular migration and invasion by inhibiting ERK1/2 and JNK activation and up-regulating the expression of COX-2. In addition, mPEBP4 overexpression inhibits Epirubicin-induced cellular apoptosis. Considering that mPEBP4 is specifically expressed in retinal ganglion cells, whether mPEBP4 is an important molecule involved in visual function needs to be further investigated.

Amino Acid Sequence↗

PubMed2006

hPEBP4 resists TRAIL-induced apoptosis of human prostate cancer cells by activating Akt and deactivating ERK1/2 pathways.

The treatment options available for prostate cancer are limited because of its resistance to therapeutic agents. Thus, a better understanding of the underlying mechanisms of the resistance of prostate cancer will facilitate the discovery of more efficient treatment protocols. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is recently identified by us as an anti-apoptotic molecule and a potential candidate target for breast cancer treatment. Here we found the expression levels of hPEBP4 were positively correlated with the severity of clinical prostate cancer. Furthermore, hPEBP4 was not expressed in TRAIL-sensitive DU145 prostate cancer cells, but was highly expressed in TRAIL-resistant LNCaP cells, which show highly activated Akt. Interestingly, hPEBP4 overexpression in TRAIL-sensitive DU145 cells promoted Akt activation but inhibited ERK1/2 activation. The hPEBP4-overexpressing DU145 cells became resistant to TRAIL-induced apoptosis consequently, which could be reversed by PI3K inhibitors. In contrast, silencing of hPEBP4 in TRAIL-resistant LNCaP cells inhibited Akt activation but increased ERK1/2 activation, resulting in their sensitivity to TRAIL-induced apoptosis that was restored by the MEK1 inhibitor. Therefore, hPEBP4 expression in prostate cancer can activate Akt and deactivate ERK1/2 signaling, leading to TRAIL resistance. We also demonstrated that hPEBP4-mediated resistance to TRAIL-induced apoptosis occurred downstream of caspase-8 and at the level of BID cleavage via the regulation of Akt and ERK pathways, and that hPEBP4-regulated ERK deactivation was upstream of Akt activation in prostate cancer cells. Considering that hPEBP4 confers cellular resistance to TRAIL-induced apoptosis and is abundantly expressed in poorly differentiated prostate cancer, silencing of hPEBP4 suggests a promising approach for prostate cancer treatment.

Apoptosis↗

PubMed2006

HDJC9, a novel human type C DnaJ/HSP40 member interacts with and cochaperones HSP70 through the J domain.

HSP40s are a subfamily of heat shock proteins (HSPs) and play important roles in regulation of cell proliferation, survival and apoptosis by serving as chaperones for HSP70s. Up to date hundreds of HSP40 proteins derived from various species ranging from Escherichia coli to homo sapiens have been identified. Here we report the cloning and characterization of a novel human type C DnaJ homologue, HDJC9, containing a typical N-terminal J domain. HDJC9 is upregulated at both mRNA and protein levels upon various stress and mitogenic stimulations. HDJC9 is mainly localized in cell nuclei under normal culture conditions while it is transported into cytoplasm and plasma membrane upon heat shock stress through a non-classical and lipid-dependent pathway. HDJC9 can interact with HSP70s and activate the ATPase activity of HSP70s, both of which are dependent on the J domain. Our data suggest that HDJC9 is a novel cochaperone for HSP70s.

Cell Line, Tumor↗

PubMed2006

Up-regulation of tumor susceptibility gene 101 protein in ovarian carcinomas revealed by proteomics analyses.

Small GTPase RAS plays a critical role in cellular signaling and oncogenic transformation. Proteomics analysis of genetically defined human ovarian cancer models identified the tumor susceptibility gene 101 (TSG101) as a downstream target of RAS oncogene. Mechanistic studies revealed a novel post-translational regulation of TSG101 through the RAS/RAF/MEK/MAPK signaling pathway and downstream molecules p14(ARF)/HDM2. Immunoanalysis using ovarian cancer samples and microtissue array revealed elevated TSG101 levels in human ovarian carcinomas. Silencing of TSG101 by short interfering RNA in ovarian cancer cells led to growth inhibition and cell death. Concurrent with the apparent growth-inhibitory effect, the levels of the CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) and hypoxia-inducible factor 1alpha (HIF-1alpha), as well as its cellular activity, were markedly reduced after TSG101 knockdown. These results demonstrate that TSG101 is important for CITED2- and HIF-1alpha-mediated cellular regulation in ovarian carcinomas.

Carcinoma↗

PubMed2006

[Quantitative method to describe the inner characteristics of hereditary nonpolyposis colorectal cancer family].

OBJECTIVE: To establish a quantitative method to describe the inner characteristics of hereditary nonpolyposis colorectal cancer (HNPCC) family. METHODS: All members of 25 HNPCC families with assembly of malignant tumors therein [with at least one patients with colorectal cancer (CRC)] in China underwent questionnaire survey. Other 32 HNPCC families with complete clinical data were collected from the published Chinese and foreign literatures related to clinical phenotype of Chinese HNPCC family. Altogether 57 HNPCC families fulfilling the Amsterdam Criteria (AC) I or II underwent analysis of the inner characteristics cumulatively. The following parameters were analyzed: familial median age when diagnosed as with the first malignant tumor (FMA-DFMT), familial median age when diagnosed as with the first CRC (FMA-DFCRC), familial proportion of CRC in first malignant tumors (FPCRC-FMT), familial proportion of CRC patients (FP-CRCP), number of involved generations, number of cancer patients, and type of family. RESULTS: In the ACI HNPCC families, the distribution patterns of both FMA-DFMT and FMA-DFCRC were not normal distribution. Most of the FMA-DFMT and FMA-DFCRC were from 35 years to 50 years with the medians of 44.0 years and 43.5 years respectively. The FPCRC-FMT and FP-CRCP were less than 0.6 in 13.2% (7/53) and 7.5% (4/53) of the families respectively. The FMA-DFMT and FMA-DFCRC were not correlated with FPCRC-FMT, FP-CRCP, number of involved generations and cancer patients, and type of family (all P > 0.05). CONCLUSION: Compared to the traditional methods, the features of HNPCC families can be accurately described by a series of quantitative parameters.

Adult↗

PubMed2006

Membrane protein hMYADM preferentially expressed in myeloid cells is up-regulated during differentiation of stem cells and myeloid leukemia cells.

We report here the molecular cloning and characterization of a novel human gene (hMYADM) derived from a human bone marrow stromal cell (BMSC) cDNA library, which shares high homology with mouse myeloid-associated differentiation marker (MYADM). hMYADM is also closely related to many other eukaryotic proteins, which together form a novel and highly conserved MYADM-like family. hMYADM with 322-residue protein contains eight putative transmembrane segments and confocal microscopic analysis confirmed its membrane localization by using anti-hMYADM monoclonal antibody. hMYADM mRNA was selectively expressed in human monocytes, dendritic cells, promyeloid or monocytic leukemia cell lines, but not in CD4+, CD8+, CD19+ cells, nor in T cell leukemia or lymphocytic leukemia cell lines. hMYADM expression was also found in normal human bone marrow enriched for CD34+ stem cells, and the expression was up-regulated when these cells were induced to differentiate toward myeloid cells. The mRNA expression level of hMYADM significantly increased in acute promyelocytic leukemia HL-60 and chronic myelogenous leukemia K562 cell line after phorbol myristate acetate (PMA)-induced differentiation. Our study suggests that hMYADM is selectively expressed in myeloid cells, and involved in the myeloid differentiation process, indicating that hMYADM may be one useful membrane marker to monitor stem cell differentiation or myeloid leukemia differentiation.

Amino Acid Sequence↗

PubMed2006

Crucial role of SDF-1/CXCR4 interaction in the recruitment of transplanted dermal multipotent cells to sublethally irradiated bone marrow.

Our previous study indicated that dermal multipotent cells (DMCs) could engraft into bone morrow (BM) of rats with sublethal irradiation and promote hematopoietic recovery after being transplanted systemically, but the mechanisms determining the recruitment of DMCs to the irradiation injured BM remain unclear. In the present study, we investigated the role of stromal cellderived factor-1 (SDF-1)/CXCR4 interaction in this process. Male DMCs were isolated and transplanted into female rats systemically, and by employing quantitative real-time TaqMan polymerase chain reaction for the sex-determining region of Y chromosome, it was found that the amount of DMCs in BM of rats with sublethal irradiation was about 3 times more than that of normal rats (P < 0.01). Incubation of DMCs with AMD3100 before transplantation, which specifically blocks binding of SDF-1 to its endogenous receptor CXCR4, diminished recruitment of DMCs to the injured BM by 57.2 +/- 5.5% (P < 0.05). In addition, it was confirmed that the expression of SDF-1 in injured BM was up-regulated when compared with that in normal BM, and in vitro analysis revealed that BM extracts from irradiated rats had a strong chemotactic effect on DMCs, which decreased significantly when DMCs were pre-incubated with AMD3100 (P < 0.05). These data suggest that transplanted DMCs were recruited more frequently to irradiation-injured BM than normal BM and the interactions of SDF-1/CXCR4 played an important role in this process.

Animals↗

PubMed2006

Molecular cloning and characterization of a novel V-ATPase associated protein, DVA9.2, from human dendritic cells.

The vacuolar proton-ATPase (V-ATPase) is a ubiquitous ATP-driven H(+) transporter that functions in numerous cell processes. Accumulating evidence shows important roles of V-ATPase in tumor metastasis and antigen presentation of dendritic cells (DC). A novel V-ATPase associated protein, designated as DVA9.2 (dendritic cell-derived V-ATPase associated protein of 9.2 kDa), has been identified from a human DC cDNA library by large-scale random sequencing. Full length cDNA of DVA9.2 encodes an 81-residue protein that shares 70-80% homology with human V-ATPase subunit M9.2. Distant relationship is also found with Vma21p, a yeast protein required for V-ATPase assembly. DVA9.2 contains a conserved domain, ATP synthase subunit H (pafm05493), and two membrane-spanning helices. DVA9.2 mRNA is detectable in several human tumor cell lines as well as some human normal cells and tissues. Moreover, the inducible expression of DVA9.2 mRNA in DC during maturation is observed. DVA9.2 displays integration with membrane and main localization in lysosome, endoplasmic reticulum and Golgi-associated organelles, only less at the plasma membrane. In addition, DVA9.2 is co-localized with V(0)-sector subunit a. Silencing of DVA9.2 by small interfering RNA (siRNA) does not affect the V-ATPase activity in cell membrane fractions or attenuate the migration and invasion in breast cancer MDA-MB-231 cells. These results indicate that DVA9.2, as a novel V-ATPase-associated protein, is not essential for the activity of V-ATPase complex and may be involved in functions of DC.

Animals↗

PubMed2006

DIgR2, dendritic cell-derived immunoglobulin receptor 2, is one representative of a family of IgSF inhibitory receptors and mediates negative regulation of dendritic cell-initiated antigen-specific T-cell responses.

Dendritic cells (DCs) are specialized antigen-presenting cells that play crucial roles in the initiation and regulation of immune responses. Maturation and activation of DCs are controlled by a balance of the inhibitory and activating signals transduced through distinct surface receptors. Many inhibitory receptors expressed by DCs have been identified, whereas the new members and their functions need further investigation. In this study, we functionally characterized DC-derived immunoglobulin receptor 2 (DIgR2) as a novel representative of a family of inhibitory receptors belonging to the immunoglobulin superfamily. We show that DIgR2 contains 2 immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within its cytoplasmic region and that DIgR2 associates with Src homology-2 domain-containing protein tyrosine phosphatases-1 (SHP-1). Blockade of DIgR2 on DCs by pretreatment with DIgR2-Ig fusion protein or by silencing with specific small interfering RNA enhances DC-initiated T-cell proliferation and antigen-specific T-cell responses both in vitro and in vivo. Furthermore, immunization of mice with antigen-pulsed, DIgR2-silenced DCs elicits more potent antigen-specific CD4+ and CD8+ T-cell responses, thus protecting the vaccinated mice from tumor challenge more effectively. Our data suggest that DIgR2 is a functionally inhibitory receptor and can mediate negative signaling to regulate DC-initiated antigen-specific T-cell responses.

Amino Acid Sequence↗

PubMed2006

New immunochemical fecal occult blood test with two-consecutive stool sample testing is a cost-effective approach for colon cancer screening: results of a prospective multicenter study in Chinese patients.

The purpose of the study is to evaluate a new immunochemical fecal occult blood test method (Hemosure IFOBT), and compare it to the Guaiac-based chemical method (CFOBT) for colorectal cancer detection. A hypothetical sequential method (SFOBT), in which IFOBT was used only as a confirmatory test for CFOBT, was also evaluated. A total of 324 patients were recruited from 5 major hospitals in Beijing, China. For each patient, 3 consecutive stool samples were collected for simultaneous CFOBT and IFOBT tests, followed by colonoscopic examination. We compared the sensitivity and specificity of the 3 methods (CFOBT, IFOBT and SFOBT) in two settings, with the first 2 consecutive samples versus all 3 samples. Although the sensitivity for the detection of cancer and large (>20 mm) or multiple adenoma was similar for all 3 methods in the three-sample setting, in the two-sample setting IFOBT had higher sensitivity than SFOBT for detecting cancer (87.8% vs. 75.5%, respectively, p < 0.05) and large (>20 mm) or multiple adenomas (65.4% vs. 42.3%, respectively, p < 0.05). The IFOBT also had a higher specificity than the CFOBT (89.2% vs. 75.5%, respectively, p < 0.01) in "normal" individuals defined by colonoscopy in the three-sample setting. Comparing two-sample setting to the three-sample setting, both CFOBT and SFOBT showed significant loss of sensitivity for the detection of cancer as well as adenoma, whereas the sensitivity for IFOBT did not change significantly. Overall, IFOBT with two-sample testing showed compatible sensitivity and specificity to the three-sample testing, and had a lower relative cost per cancer detected than the three-sample testing. In conclusion, the new Hemosure IFOBT with two consecutive stool samples appears to be the most cost-effective approach for colon cancer screening.

Adenoma↗

PubMed2006

The direct electron transfer of myoglobin based on the electron tunneling in proteins.

The electron tunneling of the protein-polypeptide interactions was observed in the study of direct electron transfer of the myoglobin (Mb) on the electrode surface. The Mb was selected as a redox active protein and gelatine was selected to couple with Mb to form an electron tunneling. The electrochemical results indicated the presence of the electron tunneling and the direct electron transfer. The circular dichroism spectra suggested that the beta-sheet chain of gelatine could interact with alpha-helical chain to form an electron tunneling to promote the protein direct electrochemistry. The SDS-PAGE results proved that the electron tunneling between Mb and gelatine was noncovalent hydrogen bonds. The immobilized Mb showed a couple of quasi-reversible redox peaks with a formal potential of -0.37V (vs SCE) in 0.1 M pH 7.0 PBS. The modified electrodes displayed a rapid amperometric response to the reduction of oxygen, H2O2, and nitrite.

Circular Dichroism↗

PubMed2006

Analysis of computational approaches for motif discovery.

Recently, we performed an assessment of 13 popular computational tools for discovery of transcription factor binding sites (M. Tompa, N. Li, et al., "Assessing Computational Tools for the Discovery of Transcription Factor Binding Sites", Nature Biotechnology, Jan. 2005). This paper contains follow-up analysis of the assessment results, and raises and discusses some important issues concerning the state of the art in motif discovery methods: 1. We categorize the objective functions used by existing tools, and design experiments to evaluate whether any of these objective functions is the right one to optimize. 2. We examine various features of the data sets that were used in the assessment, such as sequence length and motif degeneracy, and identify which features make data sets hard for current motif discovery tools. 3. We identify an important feature that has not yet been used by existing tools and propose a new objective function that incorporates this feature.

Journal Article↗

PubMed2006

Immunosuppressant triptolide inhibits dendritic cell-mediated chemoattraction of neutrophils and T cells through inhibiting Stat3 phosphorylation and NF-kappaB activation.

Triptolide, an active component purified from the medicinal plant Tripterygium wilfordii Hook F., is potent in anti-inflammation and immunosuppression. Dendritic cells (DC), one of important targets of immunosuppressants, play crucial roles in linking the innate immunity and adaptive immunity. However, the effects of triptolide on DC have not been fully elucidated. Chemoattraction of neutrophils and T cells by DC may favor their interactions and initiation of immune response. Here we demonstrate that triptolide significantly impairs DC-mediated chemoattraction of neutrophils and T cells both in vitro and in vivo by suppressing DC production of CC and CXC chemokines including MIP-1alpha, MIP-1beta, MCP-1, RANTES, TARC, and IP-10 in response to LPS. Furthermore, triptolide-mediated inhibition of NF-kappaB activation, Stat3 phosphorylation and increase of SOCS1 expression in DC may be involved in the inhibitory effect of triptolide. Our study provides a novel mechanistic explanation for the anti-inflammatory and immunosuppressive activities of triptolide.

Animals↗

PubMed2006

Neurotransmitter inactivation is important for the origin of nerve system in animal early evolution: a suggestion from genomic comparison.

Metazoans possess complicated multicellular structure among the multicellularities of eukaryotes. One evolutionary pressure that permits such complexity relates to the directed and precise informational transmission performed by numerous synapses in neuron system. Neurotransmitter inactivations play essential roles in the termination of synaptic transmission and are thus crucial for precise synaptic transmission. Here, we performed a genomic comparison among 11 eukaryotic organisms including five bilaterian species and six pan-unicellular eukaryotes to search for genes related to metazoan multicellular function. The result showed that the majority of genes related to neurotransmitter inactivation in the synaptic cleft endured high and stable selective pressure and were specifically present in bilaterians, whereas genes related to transmitter release and postsynaptic transmitter receptors did not show these properties. From these data we conclude that neurotransmitter inaction may play a critical role in the origin of the nerve system encountered in the early evolution of metazoan. In addition, we suggest that neurotransmitter inactivation probably participates in the formation or refinement of the synapse, following the concept of "ontogeny recapitulates phylogeny." Further experimental evidence is needed to support the suggestion and to explain the importance of neurotransmitter inactivation to metazoan multicellular function.

Animals↗